Novel paradigm of therapeutic intervention for skin cancer: challenges and opportunities

Background Skin cancer continues to be an imperative global health issue, urging continuous exploration of treat-ment methodologies. Conventional treatments for skin cancer include surgical interventions, immunotherapy, targeted therapy, chemotherapy, and radiation therapy. However, these methods often present obstacles like treatment resistance, systemic toxicity, limited effectiveness in advanced stages, infection risk, pain, long recovery, and impact on healthy tissue. Main body of the abstract Nanomedicine holds promise by facilitating precise drug administration, early detection, and heightened therapeutic efficiency via targeted and localized delivery systems. The integration of nanomedicine into skin cancer alleviation therapies demonstrates optimistic outcomes, including refined drug delivery, augmented bioavailability, minimized adverse effects, and potential theranostic applications. Recent breakthroughs in nanomedicine have propelled advancements in skin cancer treatment, showing significant potential in transforming the treat-ment paradigm. The presents review provides comprehensive aspects of existing skin cancer treatments and their challenges, spotlighting recent breakthroughs propelled by nanomedicine. Short conclusion This abstract delineates the present landscape of skin cancer treatments, underscores their constraints, and highlights recent strides in nanomedicine that have the potential to transform the paradigm of skin cancer treatment, ultimately elevating patient prognosis. Importantly, the present review emphasizes substantial challenges that hinder the clinical translation of nanomedicines and suggests possible remedies to surpass them.


Background
At present, cancer is a colossal global health concern, causing significant morbidities and mortalities [1].Among cancers, skin cancer stands out as the most prevalent type, presenting challenges in terms of early detection and effective treatment [2].Notably, non-melanoma skin cancer (NMSC) is a widespread global health issue characterized by a greater occurrence and increasing rates.Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) constitute the majority of skin neoplasms [3], with BCCs being more frequently diagnosed [4].The pathogenesis of BCC involves the activation of the hedgehog signaling pathway, driving cell growth and division [5].Conversely, SCCs, particularly head and neck squamous cell carcinoma (HNSCC), present a significant challenge in terms of prognosis and treatment options [6].Both types of cancer interact with the tumor microenvironment, creating an immunosuppressive state that supports tumor progression [7].Known risk factors include exposure to ultraviolet light, radiation, and immunosuppression [8].Radiotherapy is a vital treatment approach for NMSC, serving as adjuvant therapy for high-risk cases and a definitive treatment when surgery is not feasible or preferred [9].
In addition to these main types, there are less common forms of skin cancer, such as Merkel cell carcinoma [10,11], Cutaneous lymphoma [12,13] and Dermatofibrosarcoma protuberans [14].While melanoma is the most deadly form of skin cancer [15], early detection and treatment of all types of skin cancer are crucial for successful outcomes and long-term survival.
In 2020, non-melanoma skin cancer surged globally, with over a million new cases and 64,000 deaths (excluding basal cell carcinoma), notably impacting men.Australia and New Zealand reported the highest nonmelanoma rates [16].
From May 29, 2017, to December 20, 2021, a systematic review and meta-analysis were conducted to evaluate the relationship between the frequency of non-melanoma and invasive skin melanoma and occupational exposition to solar UV radiation.Analyzing 53 studies involving over 457,000 participants across 26 countries, the

Graphic abstract
findings revealed that individuals exposed to occupational solar ultraviolet radiation had a 1.45 times higher risk of developing melanoma and a 1.60 times greater risk of progressing non-melanoma cancer of skin contrasted to those with lower exposure.However, in a subgroup analysis considering different types of non-melanoma skin cancer, there was a potentially lower risk for basal cell carcinoma compared to squamous cell carcinoma [17].
Conventional methods for treating skin cancer including radiotherapy, surgery and chemotherapy have notable shortcomings, including scarring, recurrence risk, side effects, limited efficacy in advanced cases, pain, prolonged recovery, impact on healthy tissue, and infection risk.This underscores the necessity for ongoing research into more precise therapies.Nanocarriers and nanomedicines offer a groundbreaking approach, utilizing nanoscale structures to enhance drug delivery precision, increase specificity, and minimize side effects.Their potential for targeted therapy presents a promising avenue for more effective treatments with minimal impact on healthy tissues.This review outlines the current landscape of skin cancer treatments, emphasizing their limitations, and explores recent advancements in nanomedicine poised to revolutionize the treatment paradigm, ultimately enhancing patient prognosis.Furthermore, the review acknowledges challenges impeding the clinical application of nanomedicines and proposes potential solutions to address these hurdles.

Challenges in skin cancer treatment
In addressing skin cancer treatment, challenging aspects include biological barriers, delayed diagnosis in advanced stages, resistance to standard therapies, frequent recurrence, and adverse effects.Effectual drug delivery may be hindered by biological barriers, limited treatment options arise from late-stage diagnoses, conventional therapies face resistance, ongoing risks result from high recurrence rates, and patient well-being is impacted by adverse effects (Fig. 1).It is imperative to surmount these challenges to serve the purpose of progression of skin cancer treatment approaches.

Biological barriers
To heighten the therapeutic effectiveness of drugs via the means of topical delivery, understanding the skin complex biological barriers is pivotal.The primary barriers within the skin are the stratum corneum, occlusion junctions, hair follicles, and blood vessels.The stratum corneum, comprising densely packed dead skin cells, forms the outermost layer and significantly restricts drug penetration.Tight junctions regulate molecular movement between epidermal cells, influencing drug transport.Hair follicles provide an alternative route for drug permeation, while blood vessels serve as the ultimate barrier, influencing systemic drug bioavailability.By comprehending and strategizing to overcome these barriers, such as using permeation enhancers or nanosized drug carriers, formulations can be tailored to optimize drug absorption, thereby enhancing therapeutic efficacy while minimizing adverse effects [18].

Late-stage diagnosis
The primary factor contributing to fatalities from skin cancer implies the delayed detection of the ailment.Improving the chances of survival substantially hinges on early diagnosis and the subsequent application of suitable treatment.Skin cancer is typically highly manageable when identified in its early stages, but it poses greater risks and challenges if diagnosed at an advanced stage [19].
Late-stage diagnosis may result from various factors, one of which is the lack of symptoms during the initial stages, limited awareness, misinterpretation of early signs, and delays in seeking medical attention [20,21].

Resistance of conventional therapy
Resistance to conventional cancer treatments, such as chemotherapy and radiotherapy, often leads to treatment failure and tumor progression.Factors affecting treatment effectiveness include drug accessibility and genetic mutations.Researchers are exploring combined approaches, integrating chemotherapy, radiotherapy, and photodynamic therapy, to enhance treatment outcomes and reduce patient toxicity [28,29].
The emergence of drug resistance poses a significant barrier to the effectiveness of cancer chemotherapy.Targeted nanocarriers and nanomedicines may address this issue by suppressing or bypassing the overexpressed P-glycoprotein efflux pump in chemo-resistant tumor cells, potentially improving the effectiveness of anticancer drugs and enhancing therapeutic outcomes [30].

High rates of recurrence
Skin cancer recurrence, a challenge in dermatology and oncology, can result from incomplete initial removal, sun exposure, genetics, immune factors, and inadequate margins in cases like squamous cell carcinoma.To address this, ensure complete tumor removal during initial treatment, considering Moh's surgery for complex cases.Simple excision and careful pathologic examination work for early lesions.In cases of inadequate margins, postoperative radiation therapy can reduce recurrence risk.Vigilant follow-up is crucial for early detection and effective treatment [31].

Adverse effects of chemotherapy
Chemotherapy, a common treatment for various types of cancer, including skin cancer, can have several adverse effects on the body (Table 1).These effects can vary in severity and may affect different individuals differently.

Research updates in skin cancer treatment: challenges and future perspectives
The upcoming section apprise the current therapeutic frontages of skin cancer including curettage and electrodessication, cryosurgery, photodynamic therapy, immunotherapy, chemotherapy, radiation therapy and targeted drug therapy and Mohs micrographic surgery (Fig. 2).The section also emphasizes their key features, characteristic attributes, associated challenges and future prospects of these therapeutic frontages (Table 2).

Curettage and electrodessication
Diathermy combined with curettage is an effective treatment used by dermatologists for non-melanoma skin malignancies.This approach is suitable for conditions like actinic keratoses, carcinoma in situ, and select SCC and BCC under 1-2 cm in low to moderately metastatic risk areas [48].Using curettes of different diameters, the process entails methodically eliminating superficial malignancy while delivering low-amperage, high-voltage electrical energy at precise locations.Benefits of this technique include less trauma, quicker process times, and lower expenses.While cure rates may slightly lag behind standard excision or Mohs micrographic surgery, curettage and electrodessication remain valuable options for treating head and neck malignancies [49].High cure rates have been reported throughout the dermatology and surgery literatures for excision of NMSC with standard permanent section margins [50].
In a Hansen and Anderson, 136 patients (comprising 49 women and 87 men), a total of 302 basal cell carcinoma tumors, were examined.Among these individuals, 43% of the patients exhibited multiple tumors, while 21% presented with more than one tumor.Fifteen of the 136 individuals experienced recurrences, with twelve of those cases occurring within a 5-year timeframe.The 302 distinct tumors had a 5-year relapse rate of 3.97%, signifying a cure rate of 96.03% within this timeframe.When considering all available followup data, the overall recurrence rate experienced a slight increase to 4.97%, accompanied by a corresponding overall cure rate of 95.03% [49].In another retrospective analysis, 176 cancers in highrisk areas and 81 in medium-risk areas were analyzed.It found that 98.80% of patients treated for basal cell carcinomas (BCCs) did not have a relapse after 5 years, resulting in a 1.20% relapse rate.In a worst-case scenario, the non-relapse rate dropped to 79.40%, leading to a 20.60% relapse rate.The research highlighted the importance of careful treatment and found good results and cosmetic outcomes, though some patients were lost to follow-up [51].

Cryosurgery
Cryosurgery is a medical procedure that involves freezing tumor tissue using liquid nitrogen used to treat selected non-melanoma malignancies.Usually, a cotton swab or spray device are used for this, and sometimes a thermometer-carrying needle is used to ensure the targeted area reaches a sufficiently low temperature.Cryosurgery aims to quickly freeze the skin lesion and then let it defrost gradually, which results in significant damage to the tumor.In some cases, the procedure may need to be repeated for optimal results [52].
Two studies, one by Kulfik and Gage [53] and another by Kuflik [54], looked at the effectiveness of cryosurgery in treating skin cancer.The first study, which followed patients for 5 years, reported a 98.8% success rate.The second research reported the 99% recovery rate across 5 years as well as a 98.6% recovery rate in a span of 30 years after analyzing 4406 cases in 2932 patients over a 30-year period.In conclusion, these investigations have demonstrated that cryosurgery has a very high curative rate of 99% for patients with malignancies of the skin.
Another study conducted by Holt in 1988 demonstrated that cryosurgery is a safe, cost-effective, and efficacious modality for the treatment of selected nonmelanoma skin cancers, yielding excellent cosmetic outcomes with a 97% 5-year cure rate [55].

Mohs micrographic excision
Mohs excision is a specific surgical procedure employed for the extraction of various skin cancers, including common ones like melanoma also known as black tumor, SCCs, BCCs as well as rare skin tumors.In Mohs surgery, patients are typically awake as the surgeon administers local anesthesia to numb the area.The surgeon systematically removes cancerous tissue, which is then examined in a nearby lab.This cycle repeats until all cancer is removed.Afterward, the surgeon discusses options for wound closure, such as natural healing, sutures, or further procedures [56].
However combination of Mohs surgery along with a biologically engineered substance presents a viable

References
Curettage and electrodessication Employing curettes of varying sizes using a high voltage, minimal amperage electric current to systematically destroy surface lesions It is not possible to evaluate its margin because of the hypertrophic mark or keloid development, as well as the lack of pigment near the area of therapy [49] Cryosurgery Freezing tumor tissue with liquid nitrogen and causing damage to it Evaluating the margin is not practical.discomfort following surgery, soft tissue edema, Frank bleeding, hypertrophic scarring underpigmentation [55] Mohs micrographic surgery A precise surgical method that preserves the greatest amount of healthy skin while totally eliminating skin cancer cells Tumor recurrence, inaccessibility and improper orientation of excised tissue, infection, seroma, and hematoma are possible outcomes [56,98] Radiotherapy Superficial and orthovoltage X-ray therapies Past medical history involves connective tissue disorders, such as scleroderma, Gorlin condition, and recurrent tumors after radiation therapy Youthful age of less than 40 because to the possibility of developing a second cancer and a deteriorating cosmesis throughout time Anatomy, such as beneath the forearm or knee, that is vulnerable to recurrent injury or impaired circulation [60,99] Photodynamic therapy Three key elements are particularly important for non-intrusive technique: photosensitive agents, a particular laser wavelength, along with a sufficient amount of oxygen molecules Penetration of the photosensitizer, cannot completely encompass the body, variability in sunlight exposure, repeated treatments over a prolonged period of time [64,96]

Immunotherapy
Harnesses immune system to fight cancer, boosting defense Short duration of response, increased toxicity and side effects, poor efficacy and limited by resistance [100,101] Targeted therapy Precisely targets cancer cells, minimizing damage to healthy cells Chemotherapy Uses medications to destroy cancer cells in the body that are dividing quickly surgical and reconstructive alternative, reducing hospitalization time and preventing additional health issues and complications [57].
The number of cases of skin cancer patients treated with Mohs surgery showed a noticeable increase trend between 1995 and 2010, according to a retrospective study of the National Ambulatory Medical Care Survey encompassing patient visits connected to Mohs therapy.This percentage increased from around 3% in 1995 to approximately 17% in 2010 [58].
In the multicenter prospective study, Mohs surgery was used to treat 1792 skin cancer tumors in 1550 patients, follow-up was achieved for 95.3% of the tumors.There were no major complications reported during surgery or reconstruction.Minor primary postoperative complications occurred in 2.6% of cases, totaling 44 incidents [59].

Radiation therapy
For individuals with cutaneous squamous cell carcinoma (cSCC) and cutaneous basal cell carcinoma (cBCC), surgery is the main method of curative therapy.However, radiotherapy holds considerable importance in both definitive and adjuvant treatment scenarios for these patients.Various radiation techniques, such as kilo-voltage (soft) X-rays, mega-voltage electrons, mega-voltage X-rays, as well as low dose rate/high dose rate interventional radiotherapy (brachytherapy) and proton therapy, are all recognized as valid radiotherapy methods for nonmelanoma skin cancer [9,60].
Patients' responses to treatment may be improved by the addition of immunotherapy.Nevertheless, radiologists now face fresh challenges, including the emergence of unusual response patterns, pseudo-progression, and unfavorable events linked to the immune system.These issues necessitate early detection to optimize patient prognosis and treatment management [61].
In a study by Tang and colleagues, 47 patients with 54 non-melanoma skin cancers, including 42 basal cell carcinomas (BCCs) and 12 squamous cell carcinomas (SCCs), were treated with high-dose rate electronic brachytherapy.Patients received an average dose of 45.3 Gy and were followed for about 33 months.Local control was achieved in 92.6% of cases, and mild skin irritation (Grade 1) occurred in 63% of tumors, with no severe side effects.Cosmetic results ranged from fair to excellent after treatment [62].
An investigation from June 2016 to October 2019 included ten patients but was stopped early due to low enrollment.Four patients received 30 Gy of radiation in ten sessions, while six received 20 Gy in five sessions, affecting different body areas.After 1 year of follow-up, 82 adverse events were recorded, with 90% being mild to moderate.Only eight severe events (grade 3) occurred, with one linked to treatment.No serious radiotherapyrelated toxicities were reported, except for one hospitalization due to a fever [63].

Photodynamic therapy (PDT)
Photodynamic therapy (PDT) relies on three key elements: photosensitizers, specific light wavelength, and oxygen.Photosensitizers preferentially accumulate in tumor tissues.The process begins with administering photosensitizers, followed by targeted light exposure, activating them to produce reactive oxygen species.These reactive oxygen species induce cancer cell death, vascular damage, and immune response, offering a comprehensive approach to cancer treatment [64].
Nanocarriers offer several benefits for photodynamic therapy, and their seamless integration into clinical use hinges on resolving matters related to biocompatibility, toxicity, and regulatory factors [65].
A report by Lima and his team member explores the utilization of polycaprolactone nanoparticles encapsulating methylene blue for potential photodynamic therapy in treating skin cancers, specifically squamous cell carcinoma.For better skin penetration, the nanomedicine with ideal size, low polydispersion index, and excellent encapsulation efficiency were demonstrated.The spherical nanostructures were proven to have formed using scanning electron microscopy.An early burst profile consistent with the first-order model was shown by in vitro nanomedicine release, which is beneficial for combined potential photodynamic treatment and sonophoresis.The assessment of cytotoxicity and cellular uptake showed promising outcomes.A431 cell death increased with red LED light and longer incubation.The methylene blue encapsulated polycaprolactone nanoparticle likely works by generating oxygen species gradually.This mechanism supports its potential for effective treatment [66].
In a profound study, researchers developed a highly effective and minimally invasive approach for treating non-melanoma skin cancers.They encapsulated hypericin into lipid nano-capsules with favorable characteristics, including a small particle size, low polydispersity, and high encapsulation efficiency.When compared to free hypericin, hypericin lipid nano-capsules demonstrated noticeably better photoactivity, accumulation of drug-loaded lipid carrier on skin, cellular absorption, and photocytotoxicity.The researchers employed hollow microneedles for intradermal delivery of hypericin lipid nano-capsules, leading to a remarkable 85.84% tumor destruction in a nude mouse model with transplanted tumors after irradiation with 595 nm [67].
Research conducted by Zhang and coworkers explores the impact of photodynamic therapy with 5-aminolevulinic acid on skin cancers by investigating its role in autophagy regulation.Findings reveal that 5-aminolevulinic acid-photodynamic therapy, with or without 3-methyladenine or 5-fluoracil, effectively modulates autophagy, leading to the suppression of A431 and A375 skin cancer cell proliferation and the induction of apoptosis.Furthermore, the study suggests that the combination of 5-aminolevulinic acid-photodynamic therapy with 3-methyladenine or 5-fluoracil pretreatment may offer a novel therapeutic strategy for various skin cancers, including non-melanotic cutaneous cancers and melanoma [68].
In a different research, Balas and colleagues used blue light irradiance to examine the photodynamic effects of complexes produced by 5, 10, 15, 20-(Tetra-N-methyl-4-pyridyl) porphyrin tetratosylate with titanium dioxide nanoparticles on human cutaneous cells with melanoma.The photodynamic activity of the complex's was assessed using the non-malignant skin cell line CCD-1070Sk as well as the melanoma cell line Mel-Juso.Cytotoxicity manifested exclusively upon exposure to blue light of wavelength 405 nm, which was dose-dependently induced via internalized reactive oxygen species generation.Notably, the observed photodynamic effect was more pronounced in melanoma cells compared to nontumor cells, suggesting a promising avenue for selective photodynamic therapy in the context of melanoma treatment [69].
Hamdoon and colleagues studied how to improve photodynamic therapy (PDT) using optical coherence tomography (OCT) to link OCT features with treatment results.Twelve patients had OCT scans to identify tumor-free edges on 18 facial skin lesions before PDT.They monitored healing at 3, 6, and 12 months, focusing on skin layer organization and fibrosis.After treatment, OCT showed improved skin structure, with a 95% complete response rate at 12 months and 89% of patients reporting excellent cosmetic results, highlighting OCT's usefulness in enhancing PDT [70].

Immunotherapy
For a wide range of malignancies, including non-melanoma malignancies of the skin, immunotherapy is becoming a novel and exciting therapeutic option.Targeting the surface protein cytotoxic T-cell associated antigen-4 and the programmed cell death protein, checkpoint blocker antibodies primarily block proteins that control the immune system.The biomarkers that could enable selection of those patients who may benefit from these treatments, in monotherapy or in combination, are needed to be explicitly identified to avoid side effects on those expected to be non-responders [71].
Treatment for advanced melanoma has changed dramatically with the introduction of medications that can trigger the immune system to attack and kill tumor cells.Of the increasing number of immunotherapy drugs that have been approved for the management of metastatic melanoma as well as an additional therapy in stage-3 melanoma, ipilimumab, a cytotoxic T-cell antigen inhibiting antibody, was the first to provide enhanced survival in this context.Pembrolizumab and nivolumab, two antiprogrammed death-1 antibodies, are associated with a higher survival rate among individuals with advanced melanoma when contrasted with anti-cytotoxic T-lymphocyte-associated antigen-4 antibodies.These antibodies are regarded as first course of therapy for individuals with wild-type BRAF melanoma and as part of the initial course of therapy for patients with BRAF-mutated melanoma.Anti-cytotoxic T-lymphocyte-associated antigen-4 antibody treatment in combination with these medications enhance their efficacy but simultaneously increases their toxic effects [72].
In a retrospective analysis, 51 patients with advanced melanoma received immunotherapy to find out if metabolic measurements from positron emission tomography/computed tomography (PET/CT) scans could predict survival.Patients had an initial scan and two follow-ups at 3 and 6 months.Factors like tumor size, total tumor glycolysis, and tumor-to-background ratios were assessed and linked to overall survival.Measurements from the first scan could predict 3-and 5-year survival, but the most reliable indicators came from the 3-month follow-up.This emphasizes the value of metabolic data in assessing patient prognosis during immunotherapy [73].
In an interesting investigational study, cyclic peptide cRGD-functionalized chimaeric polymersomes (cRGD-CPs) were developed as a delivery system for the oncolytic peptide LTX-315 and a CpG adjuvant (synthetic DNA sequence of cytosine-phosphate-guanine that mimics the structure of bacterial DNA and activates the immune system through Toll-like receptor-9 TLR9signaling) and anti-photodynamic therapy to target melanoma cells in mice.These polymersomes showed a small size (53 nm), strong stability, and specific effectiveness against B16F10 cells.When combined with an anti-PD-1 antibody, the treatment cured two out of seven mice and triggered a strong immune response.This highlights the potential of cRGD-CPs to improve immunotherapy effectiveness against melanoma [74].
Rawson et al. conducted a study including 83 individuals from the OpACIN-neo clinical trial, in which researchers were aimed to assess the interobserver reproducibility of International Neoadjuvant Melanoma Consortium concept of histopathological evaluation and determine tumor bed features correlating with immunotherapeutic response, recurrence, and relapse-free survival.Immune-related pathological outcome and a new immunotherapeutic outcome score were the two evaluation methods that were assessed.High fibrosis in the immunotherapeutic response subtype was linked to reduced recurrence and prolonged relapse-free survival.Pathological non-response criteria were refined, and higher immunotherapeutic outcome score and immunerelated pathological outcome scores correlated with decreased recurrence.Flow cytometry analysis revealed increased B lymphocytes in high fibrosis responders.The agreement between different observers was very good when evaluating how well the treatment worked and the amount of melanoma that was still active [75].

Targeted therapy
The mitogen-activated protein kinase (MAPK) pathway (Fig. 3) is like a system of traffic lights in our cells that controls how they grow and change.When certain proteins, like NRAS, BRAF, MEK, and ERK, get switched on one after the other, it tells the cell to grow and divide.But sometimes, these signals go out of control due to mutation and can cause cancer, like melanoma.To combat this, scientists have made special medicines called inhibitors.These inhibitors work like traffic cops, blocking the signals that tell the cells to grow out of control.They are designed to target specific parts of the pathway, like BRAF, MEK, NRAS, and cKIT.These medicines have shown promise in treating melanoma and other cancers by stopping the bad signals that make tumors grow [76].
BRAF-targeted therapies, including vemurafenib, dabrafenib, and various combination therapies, have received FDA approval for treating patients with BRAF mutations.This demonstrates the pivotal role of BRAF in cancer development and treatment, marking a cornerstone in precision oncology efforts [77].
Combination therapy involving BRAF and MEK inhibition has proven highly effective for BRAF p.V600-mutant melanomas [78].When taken as a standalone treatment, the FDA-approved MEK inhibitor trametinib is suggested for the management of metastatic melanoma.Patients with a BRAF V600E mutation are eligible to receive cobimetinib in addition to vemurafenib.Binimetinib, a MEK inhibitor, shows efficacy against melanoma with NRAS mutation.The cKIT gene mutations are seldom found in acral, mucosal, or cutaneous melanoma resulting from chronic sun exposure.The cKIT inhibitors like imatinib and nilotinib Fig. 3 Depicts inhibitors that target crucial components of the RAS-MAPK pathway, which regulates cell growth.These inhibitors are tailored to address specific segments of the pathway, such as BRAF, MEK, NRAS, and cKIT.Among the cKIT inhibitors are Imatinib and Nilotinib.BRAF inhibitors comprise vemurafenib, dabrafenib, and encorafenib.MEK inhibitors consist of trametinib, cobimetinib, and binimetinib have been more extensively studied in patients with mucosal melanoma compared to those with primary cutaneous melanoma [79,80].
The phase IIIb single-arm, open-label, multicenter study reports on the effectiveness for the subgroup evaluation conducted on patients who had brain metastases from BRAFV600-mutant melanoma who were treated with trametinib and dabrafenib.Of the 856 individuals that were enrolled between March 2015 and November 2016, 32% had brain metastases, 5.68 months were the average survival without any progression.Independent variables that were associated with a reduced progression-free survival were pretreated status, ≥ 3 metastatic locations, increased lactate dehydrogenase level, and Eastern Cooperative Oncology Group (ECOG) performance status.Regression tree modeling and binary-split segmentation revealed baseline lactate dehydrogenase and ECOG performance status to be important predictive variables.These findings underscore their importance in predicting progression-free survival for BRAFV600-mutant melanoma patients with brain metastases [81].
Patients with BRAF-V600-mutant melanoma showed better survival when treated with dabrafenib plus trametinib.The analysis of 34 individuals 71 Dabrafenib and 58 Trametinib tests showed significant inter-individual differences in Dabrafenib plasma levels.There was no link detected between plasma levels of Dabrafenib or Trametinib and adverse effects, while there was a modest relationship between the two and progression-free survival.The study suggests that monitoring plasma concentration of both dabrafenib and trametinib alone may not be sufficient for assessing treatment response in patients with metastatic melanoma undergoing dabrafenib and trametinib therapy [82].
Hartman and a research collaborator investigate the development of acquired tolerance to inhibition of the MAPK pathway in individuals suffering from BRAFmutant carcinoma.The researchers created a preclinical resilience model to vemurafenib as well as trametinib using drug-naïve lineages of cells obtained from tumor tissues, exposing modifications unique to both cell lines and medications.The work highlights the adaptive character of melanoma cells by showing that many alterations associated with resistance happen instantly and at a bulk level.Novel genetic changes, including a unique frameshift variation of RNA-Binding Motifs-X, were discovered using whole-exome sequencing.The findings underscore the diverse and nuanced variability among patients in terms of resistance mechanisms, highlighting the importance of considering this diversity in developing strategies to counter acquired resistance to targeted therapies [83].
In a different publication, Labala and associates describe a new melanoma therapy strategy utilizing layer after layer constructed gold nanoparticles containing anti-STAT3 siRNA and imatinib mesylate.In melanoma, a kind of skin cancer, a protein called signal transduction and activator of transcription factor 3 (STAT3) is often active, helping the cancer to grow.Unfortunately, there are not any approved drugs to stop STAT3 yet, but scientists found that small molecules called small interference RNA (siRNA) can effectively block STAT3 production.Another protein, c-kit also known as CD117, acts like a switch on cancer cells, making them grow and resist dying.In this study, scientists used a drug called imatinib mesylate to turn off the c-kit switch and siRNA to block STAT3, with the goal of stopping melanoma growth.They put these treatments into tiny gold nanoparticles to carry them to the cancer cells.Comparing using STAT3 siRNA and imatinib mesylate separately with gold nanoparticles carrying either treatment alone, they found that combining them caused more melanoma cells to die, decreased live cells, and better stopped STAT3 activity.In tests with mice that had melanoma, applying layers of gold nanoparticles noninvasively using iontophoretic therapy on the skin showed similar effectiveness to injecting them directly into the tumor.When these gold nanoparticles were used to deliver both STAT3 siRNA and imatinib mesylate, the tumors shrank significantly, and STAT3 protein levels dropped.This indicates that layer-by-layer gold nanoparticles could be a useful way to deliver drugs through the skin, especially for combining siRNA and small molecule medicines [84].

Chemotherapy
A variety of topical therapeutic agents are used in the prevention and treatment of skin tumors and precancerous cutaneous lesions, such as imiquimod, 5-fluorouracil (5-FU), diclofenac and ingenol mebutate.These agents exhibit distinct mechanisms of action, such as promoting cell death or enhancing the immune response, targeting different types of skin cancers and precancerous conditions [85,86].
Chemotherapy is a standard treatment for advanced malignant skin cancers, employing drugs like dacarbazine, temozolomide, 5-FU, and others.While 5-FU is effective for actinic keratosis and basal cell carcinomas, its hydrophilic nature limits skin penetration.Dacarbazine, though poorly soluble with a short half-life, is a favored FDA-approved anticancer drug for malignant skin cancer.Utilizing lipid nanoparticles, encapsulated dacarbazine is topically delivered, enhancing its efficacy in treating malignant skin cancers [28].
Recent progress underscores the application of Hedgehog inhibitors Vismodegib and Sonidegib, both target at smoothened protein, a pivotal protein in the Hedgehog signaling pathway, to manage challenging BCC.Vismodegib is suitable for metastatic and locally advanced BCC, while Sonidegib is tailored for locally advanced cases, with differing dosages.Regrettably, there is a dearth of direct comparative studies for these treatments [87,88].
PD-1 (programmed cell death protein-1) inhibitor cemiplimab is the solely approved therapy for localized progressed and invasive cutaneous cancers of squamous cells currently.In cases where initial conventional treatments like cisplatin-based chemotherapies or EGFR-targeted therapies have been used, they may be considered for secondary treatment.Trials are underway to investigate different anti-PD-1 compounds and combinations of anti-PD-1 with other medications to enhance treatment options [89,90].
In merkel cell carcinoma, platinum-based chemotherapy, often with etoposide or taxanes and anthracyclines, shows initial efficacy (20-75%) but lacks lasting response and survival benefit in advanced cases [91].Immunotherapy with anti-PD-(L)-1 (Programmed death-ligand-1) antibodies should be offered as first-line systemic treatment in advanced merkel cell carcinoma [92].
For prolonged skin delivery, Nawaz and his collaborator unveiled a thermosensitive hydrogel based on chitosan and gelatin that included 5-fluorouracil-alginate nanoparticles.The nanoparticles had steady zeta potentials and ranged in size from 202 to 254 nm, exhibiting controlled release following the Korsmeyer-Peppas model.Ex vivo permeation studies show higher permeability of 5-FU alginate nanoparticles compared to 5-FU alginate nanoparticles hydrogel, yet the latter demonstrates significantly increased skin-related drug retention due to hydrogel swelling in the deeper skin layers at 37 °C.In vivo results validate maximum area under the curve, half-life, and skin-related drug retention for 5-FU alginate nanoparticles hydrogel, emphasizing its potential as an effective strategy for enhancing the bioavailability and retention of 5-FU in topical skin applications [93].
Another study performed by Pachauri and team member aimed to enhance the skin permeability and efficacy of 5-fluorouracil by developing a liposomal emulgel incorporating clove and eucalyptus oils in addition to various pharmaceutical components.Researchers developed seven formulations and evaluated them for cumulative drug release, in vitro release, and trapping efficiency.The cytotoxicity of the refined formulations against B16F10 mice melanoma cells was also assessed.Interestingly, adding eucalyptus and clove oils had a notable cytotoxic impact, suggesting increased anti-skin cancer efficacy.The synergistic impact of these essential oils improved the formulation's efficacy, leading to increased skin permeability and reduced dosage requirements for effective anti-skin cancer effects [94].
Employing 1H qNMR spectroscopy and HPLC-DAD inspection, Kugic and colleagues investigated the phenolic content of extra virgin olive oil made from native Croatian cultivars.They identified an array of 12 compounds, notably the secoiridoids oleocanthal and oleacein.The extra virgin olive oil alternative with a significant oleacein content showed strong curative properties in A375 melanoma cells while exhibiting no harmful effects in non-cancerous keratocyte cells, according to a study that investigated the biological role of the oil in melanoma cell lines.It is interesting to note that pure oleocanthal was discovered to be more secure and efficient than natural oleacein.Additionally, the research observed that post-treatment with any of the extra virgin olive oil phenolic extracts enhanced the anticancer impact of the drug dacarbazine when applied in pretreatment, without compromising the viability of non-cancerous cells [95].
With the use of micelles of d-α-tocopheryl polyethylene glycol 1000 succinate, a water-soluble vitamin E derivative, Ghezzi and colleagues sought to improve medication solubility and skin retention.The solubility of imiquimod was shown to be dependent on the form and amount of embedded lipophilic substances.The micellar formulation based on d-α-tocopheryl polyethylene glycol 1000 succinate and oleic acid demonstrated the best results, with imiquimod solubility rising to 1154.01 ± 112.78 µg/ mL and the stability lasting for a period of 6 months.Application of this formulation, either alone or in hydrogels, demonstrated delivery efficiency 42-and 25-fold higher than commercial creams, indicating its potential as a stable and effective nanocarrier for improved drug delivery [96].
In a qualitative, retroactive, and narrative investigation, Gameiro and coauthor treated 37 patients with 68 regions of actinic keratosis both the face along with scalp with Ingenol mebutate gel.Gel was applied over the course of three days on 25 cm 2 regions; baseline, day 4, 8, 15, 60, and 180 were all documented.The 100% adherence was attained, and no significant negative events were noted.On day 4, the mean ± standard deviation of the cumulative local skin response level indicated 8.61 ± 4.22.A concluding questionnaire revealed that 75.68% of patients perceived the treatment as optimum, underscoring both its well-tolerated nature and positive patient perspectives on its efficacy [97].
Improvements and ongoing research aim to address below limitations, focusing on developing more effective, targeted, and personalized treatments with fewer side effects.

Novel nanomedicines in alleviation of skin cancer: research updates
The current scenario is whipped with the research in the field of nanomedicine and targeted delivery with the purpose of treating different types of carcinomas.Nonetheless, for skin cancer, the area of nanomedicine has a lot to offer in boosting up the therapeutic efficacy of anticancer drugs via different nanocarriers including polymeric and lipid-based as discussed hereunder in this section.

Nanoparticle as drug delivery
In the recent period, notable advancements have taken place in using nanoparticles for delivering therapeutics, particularly when it comes to applications for skin cancer.The cautious administration of NP-based therapies to the outer layer of skin is necessary because it plays a dual role as an immunological and psychological barrier.The development of specialized technologies is addressing this challenge, focusing on not only the intended target, but also the specific delivery path.This has spurred the creation of a diverse range of NPbased technologies tailored precisely to handle these considerations, showcasing innovative strides in effectively navigating the complexities of utilizing the skin as a route for therapeutic delivery [102].
Due to their special abilities, which include better skin permeability, reticuloendothelial system evasion, and passive tumor-targeting through increased permeability as well as retention impact, nanoparticles have garnered a lot of interest.These NPs may be roughly classified into three groups, namely NPs based on lipids, NPs based on polymers, and NPs that are inorganic.The proportion of these nanoparticles used in recent studies between 2020 and 2023 to assess their efficacy as medication carriers for the treatment of skin cancer is depicted in Fig. 4. Inorganic nanoparticles (NPs) have specific functions, acting as therapeutic agents and drug transporters.On the other hand, lipid-and polymer-based NPs are ideal for the regulated release of a variety of medicinal compounds, guaranteeing improved penetration into the skin and other tissues, including tumor locations.This classification underscores the adaptability of NPs in targeted drug delivery, underscoring their potential in advancing therapeutic approaches [85].

Inorganic nanoparticle
Plethora of recently conducted research studies are evident of substantial potential of inorganic nanoparticle in averting the progression of cell proliferation and angiogenesis that advances massive possibilities of augmentation of alleviation of skin carcinomas in a way for convalescent manner than the existing conventional therapies (Table 3).
This study conducted by Rajendran and co-worker successfully produced stable, spherical ferulic acidsynthesized gold nanoparticles by reducing Au 3+ at pH 9.5 and room temperature, presenting potential for skin cancer treatment.The gold nanoparticles synthesized using ferulic acid demonstrated dose-dependent anti-angiogenic properties in in vivo assays utilizing the chorioallantoic membrane (CAM) model, which hindered the development of blood vessels that are essential for the proliferation of tumors.Furthermore, these nanoparticles induced programmed cell death in A431 cells, disrupted mitochondrial membrane potential, and enhanced the generation of reactive oxygen species by activating caspase-3, ultimately culminating in apoptosis [103].
In the present study, the anticancer medication 5-aminolevulinic acid was coupled with the herbal extract of Decalepis hamiltonii to efficiently create gold nanoparticles.These nanoparticles displayed minimal harm to RBC and buccal cells.When applied in photodynamic therapy against B16F10 cells, they demonstrated efficient cancer cell destruction, particularly in their conjugated form after irradiation.This process was enabled by the generation of reactive oxygen species molecules via protoporphyrin IX formation, which selectively targeted and eradicated cancer cells [104].
In a research study, Daneshvar and coworkers found an innovative method for fractionated sonodynamic therapy was developed, utilizing newly created Gold Poly(orthoaminophenol) nanoparticles as potential nano-sensitizers in combination with a multi-step, low-intensity ultrasound treatment for melanoma cancer, both in laboratory and animal models.The outcomes revealed that Gold Poly(ortho-aminophenol) nanoparticles induced dose-dependent cytotoxic effects on C540 (B16/F10) melanoma cells, and when exposed to ultrasound, they efficiently generated ROS and raised the temperature of the surrounding medium [105].
Bemidinezhad and colleagues investigated three types of nanoparticles, namely Naked Gold NPs, Glucose coated gold NPs, and Gold Liposomes, which were synthesized to possess specific size and zeta potential characteristics.The findings of the colony test showed that Gold Liposomes, at non-toxic doses, dramatically increased cell mortality in B16F0 cells when compared to gold NPs coated with glucose.This difference was shown to be significant.These results were confirmed by flow cytometry and Caspase-3/-7 action, highlighting the fact that elevated radiation sensitivity promoted apoptosis.Furthermore, Gold Liposomes were observed to increase the mRNA expression of p53, Bax, and Caspase-3/-7, while reducing the expression of Bcl-2 mRNA [106].
Yuan et al. developed a versatile fibrous membrane for post-surgical melanoma therapy, employing coreshell nanofibers with mesoporous bioactive glass encapsulating 5-fluorouracil at the core.As a result of the combined actions of the mesoporous bioactive glass nanoparticles and the PLGA shell, this novel design guarantees a progressive release of the chemotherapeutic medication, preventing sudden release.Additionally, the

SK-MEL-3 cells
Reduced the vitality of SK-MEL-3 cells in a dose-dependent way [122] mesoporous bioactive glass nanoparticles release bioactive ions, effectively preventing tumor recurrence and enhancing skin regeneration, making this membrane a promising wound dressing option for melanoma surgery [107].Through this research, polypyrrole-coated multiwalled nanotubes composed of carbon were successfully synthesized and introduced as a potential nano-sensitizer for sonodynamic therapy-based melanoma treatment, either in vitro and in vivo.The results of the experiments showed that the multiwalled carbon nanotubes caused cytotoxicity in C540 (B16/F10) cells in a dose-dependent manner.When exposed to ultrasound irradiation, these nano-sensitizers effectively elevated the medium's temperature and generated reactive oxygen species.Utilizing this multiwalled carbon nanotubes with multi-step ultrasound irradiation led to cell necrosis [108].
Doxorubicin, cerium oxide and Doxorubicin with cerium oxide in combination were encased in a hybrid matrix of polymers composed of chitosan and alginate, developed by Shurfa et al.In this, the combined formulation of Doxorubicin and cerium oxide exhibited synergistic effect on cancer cells, enhancing therapeutic efficacy rather than solitary.In vitro scratch and MTT assays revealed inhibited cell migration and significant impacts on A549 cancer cells.In vivo testing on animals with melanoma-induced skin conditions showed rapid healing and weight gain in animals treated with the cerium oxide and Doxorubicin in combination [109].
In order to improve the slow release of the hydrophobic anticancer medication camptothecin, Jae Min Jung and colleagues carried out research to create an implantable hydrogel depot using the copolymer poly-(ethylene glycol)-poly(b-aminoester urethane)-mesoporous silica NPs combination.Inclusion of this mesoporous silica NPs within the hydrogel depot copolymer facilitated better control over drug release, reducing the initial burst.The poly-(ethylene glycol)-poly(b-aminoester urethane) copolymers exhibited ionization at lower pH and temperature, forming a free-flowing complex with mesoporous silica NPs.Conversely, under higher pH and temperature conditions, they transformed into a viscoelastic gel.In laboratory experiments involving A549 and B16F10 cancer cells, the study showcased the promise of mesoporous silica NPs hydrogels in the ambience of cancer management.Furthermore, in live implantation tests and safety assessments, the research provided evidence of controlled biodegradation and the safety of the complex [110].
Another fascinating study conducted by Tavira and workmates using the blow spinning method, the research crafted a foundational scaffold from poly(ε-caprolactone), blending it with amine-functionalized mesoporous silica NPs and environmentally friendly-synthesized silver NPs loaded with doxorubicin in a gelatin solution.Examination revealed the presence of uniform nanosized particles on the fine nanofibers.The mesoporous silica/silver nanoparticles were selected especially for the doxorubicin loading process because of their excellent encapsulation efficiency and regulated release in the framework of a cancer cell microenvironment.This nanomedicine exhibited antibacterial properties against both Gram-positive and Gram-negative bacteria, showed low hemolysis potential, and effectively reduced melanoma cell division without impacting normal cells, suggesting potential for wound healing and melanoma cell management [111].
Zahraie and colleagues utilized platinum nanoparticles in their investigation for sonodynamic therapy targeting cancer cells, utilizing pulsed ultrasound radiation to avoid the drawbacks of continuous ultrasound exposure.Gas storage in a platinum-based material generates cavitation sites, enhancing sono-sensitization.Platinum nanoparticles in conjunction with a 70% decrease in the ultrasonic radiation pulse ratio efficiently impede the growth of C450 cancer cells without raising the temperature of the surrounding cells, guaranteeing safety.Sonodynamic therapy with platinum nanostructures generates reactive oxygen species, reducing the reliance on hyperthermia.A combination of platinum nanostructures and ultrasound radiation at a 30% pulse ratio over 10 min is proposed as an effective cancer treatment method [112].
Raj and associates demonstrated that a silver nanoparticle as nanogel mediated by the flower extract of Calotropis procera, effective for skin cancer patients.MTT assay done on A431 cells to confirm anticancer activity which shows decreased in cell viability with increasing concentration.This natural extract exhibits significant antioxidant activity.The nanogel found safe, compatible with skin, possesses strong antimicrobial, antioxidant, and anticancer properties [113].
With an average size of 61 nm and zeta potential of -18mv, Alstonia angustiloba extracts were effectively incorporated into silver nanoparticles (NPs) by Rahim and colleagues in a research investigation, guaranteeing persistent engagement with malignant cells.A. angustiloba silver nanoparticles and the extract from Alstonia angustiloba shown cytotoxicity against A431 cells that was dose and time-dependent.Impressively, A. angustiloba silver NPs demonstrated strong anti-proliferative effects in a shorter treatment duration.Both the extract and A. angustiloba silver NPs induced apoptosis and DNA cell cycle arrest, underscoring their potential as anti-neoplastic agents [114].
Chuen et al. developed sodium alginate non-stoichiometric silver sulfide NPs, with a diameter of 40-50 nm, and effectively produced them by microwave heating.
Silver nitrate, sodium alginate, and sulfur particles with micron sizes were combined with water; sodium alginate performed the dual roles of stabilizing and reducing agent.This method produced sodium alginate non-stoichiometric silver sulfide NPs, which effectively absorbed 980 nm near-infrared light, by enabling the quick reduction of silver nitrate by alginate.A noteworthy photothermal conversion yielding more than 60% was demonstrated by these nanoparticles.In vitro experiments revealed that, in conjunction with 980 nm near-infrared light at 700 mW.Sodium alginate non-stoichiometric silver sulfide NPs drastically reduced A431 cancer cell viability to 14%, compared to 80% in the control group [115].
A potential strategy for sustainable nanomedicine is the eco-friendly and economical bio-assembly of silver nanoparticles by Himalini and associates utilizing fungal extracts, namely Fusarium spp.silver nanoparticles having a mean size of 4 nm were created in this work employing a fungus extract called F. incarnatum.These silver NPs displayed strong antimicrobial and anti-melanogenic properties when tested on SK-MEL-3 human skin melanoma cells at low concentrations, highlighting their potential for pharmaceutical applications [116].
In a study, Rana and colleagues examined a peptidedrug nano-construct as a potential treatment for skin tumors induced by DMBA/TPA in female BALB/c mice.This nanostructure was made of oligomeric silver nanoparticles coated with chitosan and co-loaded with nisin and 5-FU.The findings demonstrate the promise of combining these two different anticancer agents on a single platform for effective in vivo anticancer therapy [117].
Tambunlertchai and co-authors chemically synthesized silver nanoparticles, It caused apoptosis in melanoma cell lines, such as mouse-derived B16.F10 and humanderived A375, demonstrating anti-melanoma capabilities.The combination administration of silver-NP and Resiquimod enhanced the longevity of C57BL/6j female mice with melanoma in live animals.It was discovered that CD8 + T-cells contributed to this outcome.Notable changes in gene expression linked to immunological activation, inflammatory processes, and cell proliferation were found by NanoString screening.Crucially, the treatments with silver-NP and resiquimod were found to be safe for the mice [118].
Kaimuangpak and associates successfully produced phyto-nanomedicine candidates by employing green synthesis for nanoparticles.It showed a definite connection between the bioactivity of the nanoparticles and the plant isolate Cratoxylum formosum Pruniflorum.Silver NPs exhibited significant pharmacological properties, such as antioxidative, antibacterial, and in vitro anticancer effects on human melanoma SK-MEL-2 cells.While the NPs showcased these properties, the medicinal plant Cratoxylum formosum Pruniflorum played a pivotal role as coating, size reduction and stabilizing agent in green synthesis of nanoparticles [119].
Jevapatarakul and colleagues produced Zinc oxide NPs which displayed significant anticancer activity against non-melanoma skin cancer cells (A431) and cancerous keratinocytes (HaCaT), with no adverse effects on normal cell lines (Vero).Notably, Zn-oxide nanosheets exhibited stronger cytotoxic effects on A431 cells compared to spherical Zn-oxide particles.RNA-sequencing analysis revealed alterations in gene expression related to cancer and MAPK signaling pathways in A431 cells when exposed to Zn-oxide nanosheets [120].
Chelladurai and their associates explored Alpinia calcarata rhizome extract for phytochemicals and utilized it as a reducing agent to create Zn-oxide NPs with potential applications in biomedicine and therapy.The findings from the MTT assay, a test often referred to as the "3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide" assay, and the visible changes in cell appearance related to cell death (apoptosis) using acridine orange/ ethidium bromide staining suggest that more cells in the human epidermoid neoplasm A431 cells underwent apoptosis and necrosis when treated with Alpinia calcarata Zn-oxide nanoparticles compared to cells treated only with the plant rhizome extract.This highlights their potential as potent antimicrobial and anticancer agents [121].
In another study conducted by Vakayil and colleagues, they developed zinc oxide NPs using rhizome extracts of Acorus calamus.Additionally, they fabricated fabrics coated with these Acorus calamus zinc oxide nanoparticles, demonstrating strong antimicrobial properties against pathogenic microbes.The study utilized optical microscopy and MTT assays to assess the apoptotic and anti-proliferative effects of Acorus calamus zinc oxide NPs on SK-MEL-3 melanoma cells.The findings revealed that Acorus calamus zinc oxide NPs effectively reduced SK-MEL-3 cell viability in a dose-dependent manner [122].

Polymer-based nanoparticles
Researchers have thoroughly examined polymer-based nanoparticles, and several investigations have revealed them to hold a very effective treatment for skin cancer.(Table 4).
In a study, Barbosa et al. highlight the benefits of using poly-(lactic-co-glycolic acid)-NPs for photodynamic therapy against malignant melanoma B16-F10 cells that harbor hydrophobic Protoporphyrin IX.Significantly, the study reveals that a low drug concentration of 7.8 µg/ ml proves highly effective when Protoporphyrin IX is encapsulated within PLGA NPs, and notably, this treatment is found to be non-cytotoxic in the absence of light.One important element in the PDT process is the buildup of Protoporphyrin IX within the cells, which when faced with light, starts the synthesis of reactive oxygen species.These ROS, in turn, trigger apoptosis and tissue necrosis, underscoring the essential role of Protoporphyrin IX accumulation in the effectiveness of PDT for treating malignant melanoma [123].
In a study, Jing and colleagues highlighted the bioavailability challenges of resveratrol arising from its rapid in vivo metabolism and degradation.To overcome this hurdle, they developed innovative resveratrol nanoparticles by utilizing mPEG-PLA nanoparticles to encapsulate both conjugated and free forms of resveratrol.Under physiological settings, this strategy produced a prolonged release profile and increased drug loading.Conjugated resveratrol NPs did not perform as well as encapsulated resveratrol NPs did in vitro tests using B16-F10 cancer cells, perhaps due to restricted biotransformation in simpler cell models.In an in vivo study involving C57BL/6 J mice with subcutaneous B16-F10 melanoma, intraperitoneal administration unveiled a connection between enhanced plasma stability, reduced liver metabolism, and the suppression of tumor growth [124].
In order to generate potent antitumor immune responses, Yudi Xu and his colleagues in this study created the mannan-adorned pathogen-like polymeric nanoparticle that served as a protein vaccine carrier.A core-shell structure was used in the creation of the nano-vaccine.The outside shell was composed of mannan, while the center was a nanoparticle made of polylactic acid and polyethylenimine.Electrostatic interactions allowed protein antigens and the Toll-like receptor-9 agonist CpG to bind to the PLA-PEI core.The concentration of nano-vaccines in lymph nodes was significantly enhanced by mannan augmentation, particularly in CD8 + dendritic cells.Mannan also promoted dendritic cell maturation in conjunction with CpG, which led to strong tumor-specific immune responses in vivo.In various murine tumor models, a solitary administration of this nano-vaccine produced remarkable antitumor outcomes, leading to a 50% cure rate among mice and the establishment of immune memory capable of resisting tumor re-challenges [125].
Thi and associates in their study cantered on developing dendrimeric micelles for treating melanoma by encapsulating paclitaxel with curcumin.Using cholesterol and histidine-arginine dipeptides in PAMAM dendrimers, the researchers found that cholesterol had no discernible effect on the bioactivity of the micelles.But it turned out that adding Polyethylene glycol tocopherol succinate (TPGS) was essential for improving the physicochemical properties, drug encapsulation effectiveness, and sustainability of the micelles.When dendrimeric micelles were added to TPGS, curcumin was effectively encapsulated, increasing its bioavailability.Dendrimeric micelles loaded with paclitaxel boosted cell mortality when compared to paclitaxel alone, while dendrimeric micelles loaded with curcumin had a stronger anticancer impact than free curcumin, according to in vivo investigations.In essence, the study underscores TPGS's pivotal role as a key excipient in dendrimeric micelles, offering a promising avenue for enhancing drug delivery and therapeutic efficacy in melanoma treatment [126].
The clinically licensed anticancer medications dabrafenib along with vemurafenib, which are intended to precisely target BRAF in melanoma patients, were effectively encapsulated into nano-micelles by Russi and colleagues.An amphiphilic dendrimer's themselves produced these micelles.The assembly procedure produced around 10-nm-diameter core shell nano-micelles.The nano-micelles showed remarkable drug loading capacity of about 24 percent for vemurafenib and approximately 27% for dabrafenib, in addition to remarkable encapsulation yields of nearly 70% for dabrafenib and 60% for vemurafenib.Both medicines had improved potency, 2-3 times larger than that of the freely given therapeutic medications, in melanoma cell line experiments in vivo, as evidenced by the concentration-dependent reduction in cell growth.A viable path forward for enhancing the therapeutic effect of BRAF-targeting medications in the treatment of melanoma is this nano-micelle-based encapsulation technique [127].
Azhar and associates created the nano-micelles by encasing β-carotene, a phytochemical known for its benign anticancer effects, in thiolated chitosan and lithocholic acid.With regard to β-carotene, the nano-micelles demonstrated remarkable entrapment along with loading capabilities of 64% & 58%, respectively.In vitro assessments indicated that the nano-micelles provided a stable, efficient, and safe mucoadhesive formulation.In vivo investigations demonstrated a significant retardation in the growth of skin cancer.The findings suggest that these nano-micelles, comprising thiolated chitosan and lithocholic acid, loaded with β-carotene present a promising avenue to enhance the pharmaceutical and pharmacological attributes of this anticancer agent, with potential implications for the treatment of skin cancer [128].

Lipid-based nanoparticles
Owing to the biocompatibility and biodegradability of lipids, lipid-based nanoparticles are one of the best considered nanocarrier candidates among other nanomedicine approaches.There are distinct account of studies that establish the plausible role of lipid-based nanocarriers in enhancing the therapeutic efficacy of loaded anticancer drugs (Table 5).
A transdermal drug delivery system called Paclitaxelmultistage targeted liposomes Gel for melanoma treatment was developed as a consequence of Yifei Ni and colleague's investigation, which incorporated multistage targeted liposomes within a hydrogel matrix.Improved permeability throughout the stratum corneum was shown by these prepared liposomes, which also showed remarkable deformability, quick endocytosis, and transcytosis abilities.In vivo assessments substantiated the safety and effectiveness of Paclitaxel-multistage targeted liposomes Gel, presenting it as a promising formulation for therapeutic use in melanoma [129].
In a research, Pivetta and associates examined the properties of liposomes that were created using a variety of lipids and either with or without surfactants to encapsulate photosensitizers such as acridine orange and  Exhibit significant PDT activity, reducing the cell viability to 11% [138] methylene blue.Thin-film hydration was used to make liposomes, and extrusion was then used to reduce the particle size.The findings demonstrated that, independent of the presence of surfactants, the stability of liposomes was dependent upon their lipid makeup.The liposomes that coupled cholesterol with sodium cholate or Span 80 surfactants to improve stability and encapsulate acridine orange and methylene blue had the highest level of resilience.Encapsulation efficiency studies demonstrated acridine orange strong affinity, resulting in high encapsulation efficiency (> 98%), while methylene blue encapsulation was generally moderate (63-86%).Notably, acridine orange liposomes exhibited heightened phototoxicity on MET1 squamous cell carcinoma cells, achieving an IC50 similar to the free drug, indicating their potential effectiveness in cancer treatment [130].
Charankumar and team member's created pioglitazone-loaded liposomes into a gel of hyaluronic acid to create an acidic pH-responsive reservoir.The hydrogel displayed sustained drug release over 24 h in vitro.Studies on cellular internalization revealed liposome penetration into melanoma cells, inducing nuclear fragmentation and apoptosis.Ex vivo skin permeation assessments affirmed depot formation, confining liposomes to the upper skin layer and preventing unintended systemic exposure.This method presents a promising strategy for precisely controlled Pioglitazone delivery in melanoma therapy [131].
Zhu and coworkers in his research explored a novel microfluidic chip-based method was devised to optimize the encapsulation efficiency and stability of Curcumin-loaded liposomes.These liposomes created a system allowing topical melanoma therapy in addition to skin penetrating proteins.In vitro experiments demonstrated that (0.5 mg/mL curcumin liposomes with TAT solutions) promoted Curcumin skin penetration, demonstrating improved lesion invasion and inhibition during anticancer assays using the B16F10 cell line.Moreover, the application of (0.5 mg/mL curcumin liposomes with TAT solutions) gel in vivo effectively suppressed melanoma growth without impacting mouse weight, inducing tumor cell apoptosis within tumor tissues.This highlights its potential as a safe and efficient approach for topical melanoma therapy [132].
Denise and colleagues carried out this research to optimize nanostructured lipid carriers using chloroaluminum phthalocyanine, enabling effective photodynamic treatment in malignancies of the skin.NLCs formulation identified as the most stable, containing glycerol monostearate and polyvinyl alcohol.Another NLCs formulation functionalization with chitosan aimed to improve encapsulation efficiency and stability.While NLCs demonstrated biocompatibility, similar release profiles, cellular uptake, and permeation enhancement, the photodynamic efficiency of NLC functionalization with chitosan was lower than uncoated NLC containing glycerol monostearate and polyvinyl alcohol.In BF16-F10 melanoma PDT, NLC containing glycerol monostearate and polyvinyl alcohol effectively reduced cell viability to 70%, while NLC functionalization with chitosan achieved 50% [133].
Using Central Composite Rotatable Design, Imran and colleagues created and optimized drugs loaded NLC gel containing resveratrol along with quercetin.When compared to a conventional gel, the NLC gel showed a significant threefold increase in drug distribution in the epidermal and dermal layers.Cytotoxicity assessments on A431 human epidermoid carcinoma cells indicated a significantly lower half-maximal inhibitory concentration (IC50) of 86.50 µM for the NLC gel, highlighting its potential as a more effective therapeutic option for dermatological applications [134].
In another research study, Rapalli and colleagues created Curcumin-NLC via Hot Emulsification and Probe Sonication, which produced a longer in vitro release that lasted as long as 48 h as opposed to free curcumin, which released completely in 4 h.Studies on ex vivo skin permeation revealed that Curcumin-NLC gel outperformed free curcumin gel in terms of both skin retention and penetration by a remarkable 3.24 times.Studies on cell viability showed that the formulation was safe for HaCaT cell lines.Even with a very high dose of 8 µM concentration, more than 50% of the cells remained viable when treated with both the curcumin NLC dispersion and the free curcumin solution.This suggests that Curcumin-NLC has the potential for sustained release and improved penetration into the skin [135].
Using 5-fluorouracil and resveratrol, Kashif and his colleague developed and refined a synergistic NLC gel with the goal of improving skin penetration for increased efficacy against skin cancer.The improved lipid nanosystem exhibited significantly enhanced, slow, and prolonged drug release, following non-Fickian Higuchi kinetics.Combinatorial optimized lipid nanosystem containing 5-fluorouracil and resveratrol demonstrated superior efficacy on the A431 cell line compared to the conventional formulation [136].
In their work, Hasan et al. created NLC gel that included cannabidiol as well as 5-fluorouracil, therefore introducing a unique therapeutic value.In both in vitro and ex vivo experiments, the improved NLCs-which have a zeta potential approximately -34 mV and a particle measuring 206 nm in diameter facilitated efficient penetration into epidermal layers.Comprehensive cell viability assessments, including MTT assays and wound healing studies, underscored the superior efficacy of NLCs containing 5-fluorouracil and cannabidiol compared to conventional formulations.Dermatokinetic studies confirmed enhanced drug deposition in the epidermal and dermal layers, with a particularly significant reduction in cell viability observed against the A431 human epidermoid carcinoma cell line [137].
Solid lipid nanoparticles encasing daphnetin and its synthetic equivalent, 7,8-dihydroxy-4-methyl-3-(4hydroxyphenyl)-coumarin (DHC), were designed with remarkable encapsulation efficiency by Katopodi and colleagues.The nanoparticles showed good stability in aqueous dispersion, with a mean hydrodynamic size of about 250 nm.Both coumarin analogs and their SLNs exhibited enhanced antioxidant activity and demonstrated significant photodynamic therapy efficacy against the A431 cell line, with DHC coumarin reducing cell viability to 11% after irradiation [138].

Gold nanoparticle photothermal therapy
Gold nanoparticle-based photothermal therapy (PTT) in cancer treatment has evolved, now often combined with immunotherapy, chemotherapy, and photodynamic therapy, departing from standalone applications.Gold nanoparticles possess highly effective photothermal transducer properties, efficiently absorbing near-infrared light due to their unique structural dimensions.Gold nanoparticles used for photothermal therapy can help sensitize cancer cells to chemotherapy, regulate genes, and enhance immunotherapy by improving cell permeability and delivery inside cells.The process of cell death, either necrosis or apoptosis, depends on the laser power and temperature reached within cancerous tissues during treatment.It is crucial because cells that die from necrosis may promote secondary tumor growth, while those that die from apoptosis could trigger an immune response to prevent the growth of secondary tumors.To overcome in vivo barriers, gold nanostructures are modified with targeting ligands and bio-responsive linkers [139].
For photothermal therapy, gold nanoparticles are perfect because of their adjustable near-infrared absorption and distinctive surface plasmon resonance.They possess enhanced absorption, scattering, tunable optical features, and tumor-targeting abilities, positioning them as highly promising agents in cancer therapy [140].In Table 6, two studies illustrate the therapeutic effectiveness of gold nanoparticles utilizing photothermal therapy.
Singh and coworkers developed biodegradable liposome gold NPs incorporating curcumin with encapsulation efficiency around 70% and liposome gold nanoparticles was synthesized and Photothermal mediated cytotoxicity was evaluated on B16F10 melanoma cell line.The cytotoxicity of Curcumin-loaded liposome gold NPs and liposome gold NPs was enhanced to ~ 90% and ~ 80% respectively upon laser irradiation for a duration of 5 min [141].
Suarasan and colleagues conducted a study wherein they synthesized gold nano-triangular nanoparticles (AuNTs) with localized surface plasmon resonance bands oriented at wavelength of 690, 780, and 890 nm.These AuNTs, designated as AuNTs-690, AuNTs-780, and AuNTs-890, respectively, were evaluated for their ability to affect melanoma cells phototherapeutically.The results of this colorimetric assay were used to determine the viability of the cells.A decrease in cell viability to 88 and 82% is noticed for the cells treated with AuNTs-690 and AuNTs-780, compared to the control cells [142].

Nanogels
Nanogels hold significant promise for targeted drug administration in the treatment of skin cancer, possessing regulated swelling characteristics, thermodynamic stability, and good drug entrapment effectiveness.They exhibit responsiveness to both internal and external triggers like radiation, ultrasound, enzymes, and pH changes, facilitating precise drug release.This adaptability is crucial for effectively delivering drugs with short half-lives and rapid enzymatic degradation.Furthermore, nanogels offer the potential for active targeting through surface modifications for attaching targeting molecules.When specific polymeric elements are strategically incorporated, conventional polymeric nanogels can transform into advanced stimuli-responsive nanogels, dynamically adjusting their properties based on stimuli.This ability allows for efficient concentration of anti-neoplastic biomolecules at the targeted site, enhancing drug delivery effectiveness and minimizing adverse effects in skin cancer therapy [143,144].These are separate reports of studies that establish the potential contribution of nanogels in improving the therapeutic effectiveness of loaded anticancer drugs (Table 7).
A research study by Sabitha and colleagues focuses on developing and evaluating chitin nanogels loaded with 5-fluorouracil.Nanogels showed pH-responsive enlargement and release of drugs.They had spherical particles that ranged in size from 120 to 140 nm and stable water dispersion.Chitin nanogels loaded with 5-fluorouracil selectively exhibited toxicity against melanoma-A375 cells, while displaying lower toxicity toward human dermal fibroblast cells.Experiments on skin penetration revealed that while FCNGs had a steady-state flow comparable to control 5-FU, their retention in deeper skin layers was four to five times higher.Histopathological evaluation revealed loosening of the horny layer of the epidermis due to the interaction of cationically charged chitin, with no signs of inflammation [145].
In order to distribute curcumin for the treatment of skin cancer, Priya and his colleagues created carboxymethyl cellulose-casein nanogels with a layer-by-layer covering of folic acid and casein.The composition of the nanogels and their amorphous drug dispersion were validated by using XRD, FTIR, cryo-SEM, and TGA.In an acidic pH, NGs showed layer-by-layer enhanced swelling and release of drugs.Studies on cellular absorption showed that NGs coated with bilayers of casein and folic acid were more readily absorbed, leading to greater cytotoxicity and apoptosis against folate receptor-overexpressing MEL-39 melanoma cells.Additionally, casein and folic acid coated NGs exhibited favorable skin penetration and retention across all skin layers [146].
In a study, Sahu and associates created a pH-responsive nanogel comprised of chitosan that was capable of encasing a modest dosage 0.2%w/v of 5-fluorouracil and showed promise in treating melanoma.This ion gelationsynthesized nanogel exhibits persistent release of drugs and nanosize particles.Safety was confirmed through hemolysis and coagulation analysis, while MTT and Nanogel 5-FU -Human basal cell cancer line//male albino mice Biosafety and good antitumor effects [152] apoptosis assays highlighted efficacy.In vivo assessment in mice, gamma scintigraphy, and immunohistochemistry revealed selective melanoma targeting, improved skin regeneration, and alignment compared to standard 5% 5-fluorouracil and control groups [147].
Shen and Qiu conducted a study in which they developed a versatile nanogel through the collaboration of alginate and TAT peptide using a technique of merging via blending.Alginate as well as TAT peptide worked together to provide improved mucus penetration in the gut, more stable in abdomens, and efficient transfer between MDCK cells as well as mucus layers.Immunization in C57BL/6 mice demonstrated elevated Interferon gamma secretion, enhanced cytotoxic T-cell activation, and a notable 42.5% inhibition rate against B16F10 tumors with this oral DNA vaccine [148].
Niosomal nanogels were created by Mahmood et al. by properly preparing niosomal NPs loaded with 5-fluorouracil, which were subsequently encapsulated with chitosan and conjugated using tripolyphosphate.Characterization revealed nanoscale sizes ranging from 165.35 ± 2.75 to 322.85 ± 2.75 nm, positive zeta potentials, and high encapsulation efficiency around 92%. Chitosan-coated formulations demonstrated controlled drug release over 72 h, exhibited hemocompatibility, and showed potent anticancer activity against B16F10 cells with lower cytotoxicity toward NIH3T3 cells compared to pure 5-FU [149].
Ding and teammates in his study introduces a nanogel designed for high drug loading of Thymopentin and Doxorubicin, ensuring site-specific and controlled release with minimal side effects.The liberated doxorubicin triggers immunogenic cell apoptosis and tumor cell death, hence initiating the immunological response.Thymopentin promotes the proliferation and differentiation of dendritic cells and T-lymphocytes, resulting in outstanding immunotherapeutic efficacy against melanoma metastasis [150].
In order to create nano-lipid carriers, Badalkhani and associates used liquid lipids like carrot seed oil and the powerful antioxidant gamma oryzanol in addition to naturally occurring solid lipids like shea butter & beeswax.With a particle size of less than 150 nm, excellent homogeneity (PDI = 0.216), an elevated zeta potential (− 34.9 mV), a pH of 6, a stable structure, 90% entrapment efficiency, and precisely controlled release, these NLCs were ideal for topical administration.A rat model showed that the ultimate nanogel formulation, which included NLCs along with nano-UV filters, had no skin irritation or sensitization, great photoprotection (SPF = 34), and good prolonged storage stability.Thus, the developed formulation proved effective for skin protection and compatibility [151].
For a unique approach to treating skin cancer, Mihaela et al. created novel topical gel formulations that included hyaluronic acid plus sodium alginate as well as AS1411 aptamer-functionalized polymeric nano-capsules containing 5-Fluorouracil.Enhanced permeability of 5-FU was proven by the gel formulations with non-irritating nano-capsules by ex vivo permeation through chicken skin membranes.In vitro cytotoxicity assays on a human basal carcinoma cell line revealed significant cytotoxic effects of the formulations loaded with 5-Fluorouracil [152].

Nanoparticle-based sunscreen
Globally, there is a rising incidence of cutaneous melanoma, with sun exposure recognized as a significant modifiable risk factor [153].Outdoor athletes run the danger of overexposure to the sun, which can lead to sunburn, solar damage, and an increased risk of skin malignancies such as malignant melanoma, squamous cell carcinoma, and basal cell carcinoma.It is crucial for individuals to comprehend the significance of employing proper sun protection measures and being well-informed about the risks linked to these specific types of skin cancers [154].
Since its introduction almost a century ago, sunscreen has become an essential component of global sun protection strategy.The reason for its effectiveness in reducing the harmful effects of UV radiation is its ability to absorb, reflect, and deflect sun rays.This capability enables sunscreen to play a crucial role in reducing the occurrence of skin disorders caused by UV radiation, ultimately contributing to a significant decrease in their frequency [155].UV filters are vital components in sunscreens, offering protection against solar radiation.Avobenzone prevails as the most utilized UV filter, with bis-ethylhexyloxyphenol methoxyphenyl triazine usage doubling in 2021.The TiO 2 , an inorganic UV filter, has seen a rise in usage as well [156].Scientists have extensively investigated nanoparticle-based sunscreens and UV filters, and numerous studies consistently affirm them as a highly promising strategy for preventing skin cancer.
In a study by Md.Shabbir Alam and workers reported that Rutin-loaded glycerosomes nano-sunscreen formulation particle size ranging 123.7 ± 7.85 was stable, highly safe, and had good sun protection factor values that could be used as a suitable option for topical drug administration to maximize the therapeutic efficacy of the drugs [157].
Chuntao and colleagues presented a study on sunscreen nano-capsules loaded with EHA (2-Ethylhexyl-4-dimethylaminobenzoate), highlighting their promising potential for sunscreen products.The formulation demonstrated sustained release capabilities and a high sunscreen effect, indicating its suitability for effective and long-lasting sun protection [158].
Reinosa and colleagues conducted a study employing the sol-gel method, where they developed a hierarchically structured composite with a safe-by-design approach.This composite consisted of titanium dioxide TiO 2 microparticles with zinc oxide ZnO nanoparticles securely attached.This composite, designed to mitigate the drawbacks of inorganic nanoparticles, demonstrates superior UV absorption compared to individual TiO 2 or ZnO components.When incorporated into sunscreen, the composite maintains a 50% higher Solar Protection Factor over time, minimizing photodegradation.This unique combination of oxides not only enhances UV attenuation but also hinders the adverse effects of free radicals, presenting a novel avenue for effective UV absorbers without the drawbacks of photocatalysts [159].
Gelatin nanoparticles containing rutin were created for sunscreen compositions with particular components through a study conducted by Areias et al.These rutinloaded gelatin NPs demonstrated a 74% rise in antioxidant activity and a 48% increase in Sun Protection Factor, indicating their promise as bioactive sunscreen materials.Nonetheless, safety concerns arose as both Gelatin NPs and glutaraldehyde exhibited a concentration/timedependent decrease in HaCaT cell viability [160].
Shu-Xian Li and his colleague's research investigation developed an organic acid-extracted natural, broad-spectrum photoprotective agent from lignin.Sub-micrometer particles, derived from different pretreatments, were integrated into sunblock formulations.These organic acid lignin sub-micrometer particles, which were identified by spectroscopy, significantly raised lotion sunscreen protection factor levels by 2.80-3.53 at a 5% dose, indicating potent UV-blocking properties.With UVA/UVB values ranging from 0.69 to 0.72, the particles exhibited superior properties, highlighting their potential in sun protection [161].

Nanoparticle-based imaging and diagnosis
Nanomedicine has shown great promise in various fields, including healthcare and diagnostics.In the context of skin cancer imaging and diagnosis, nanomedicine offers innovative solutions for improving early detection, enhancing imaging techniques, and enabling targeted therapy such as melanoma [162].Inorganic theranostic nanotools, including quantum dots, gold and silver nanoparticles, and superparamagnetic iron oxide NPs, serve as effective signal emitters and contrast agents for advanced imaging modalities such as MRI, optical coherence tomography, and confocal imaging, enabling highly sensitive and biocompatible cancer imaging without eliciting allergic or immune responses [163].
Theranostic liposomes [164], capable of loading diverse diagnostic nanoparticles and anticancer drugs, play a pivotal role in cancer diagnosis and therapy.Breakthroughs in molecular imaging of proteases have significantly advanced cancer diagnosis [165].Hybrid nanoplatforms, merging materials, enhance functionality for gene/drug delivery, immunotherapy, molecular diagnostics, and bio-imaging, revolutionizing cancer research and treatment [166].
The field of skin cancer nano-theranostics and imaging has a bright future ahead of it, with highly individualized, accurate, and least invasive methods for skin cancer detection, therapy, and follow-up predicted.These developments have the potential to significantly improve patient outcomes and lower the incidence of skin cancer worldwide.

Nanoparticle-based gene therapy
Treating skin cancer with nanoparticle-based gene delivery has proven to be a very successful approach.Novel nano-formulations for gene delivery are made by encasing nucleic acids such as oligonucleotides, plasmid DNA and small interfering RNA within nanosystems such as liposomes, polymers and cell-penetrating peptides.These formulations show promise in various therapeutic approaches [167].
Interferons exhibit therapeutic potential in different types of skin cancers, including squamous cell carcinoma, basal cell carcinoma, and melanoma [168].Recent advancements in technology have put the Stimulator of Interferon Genes (STING) pathway in the spotlight for cancer treatment.This pathway was first discovered in 2008 as a defense mechanism against viruses in our cells.Now, it is gaining attention for its ability to fight different types of cancer and improve cancer treatments.STING helps increase the production of type 1 interferon, which is important for the body's response to cancer.Along with triggering inflammatory processes and resisting tumor formation, STING is crucial for fighting off invaders.ADU-S100 is a synthetic compound that activates the STING pathway, promoting immune responses against cancer cells.In a Phase 2 clinical trial for patients with head and neck cancer, ADU-S100 was tested for its safety and effectiveness.Another potential treatment involves injecting mRNA-lipid nanoparticles containing active STING mutants into cancer cells to boost antitumor immunity and encourage cancer cell death [169].
In an interesting study it was deciphered that in the complex landscape of skin cancer, non-coding RNAs play a significant role.Different kinds of non-coding RNAs modulate vital cellular processes that underlie the development of illness by acting as regulators, either as tumor suppressors or oncogenes.Understanding the mechanisms of non-coding RNAs dysregulation offers actionable insights into disease progression and unveils potential therapeutic targets for skin cancer [170].
Meng Wang and colleagues aimed to uncover the molecular mechanisms driving melanoma proliferation, seeking effective interventions to enhance clinical outcomes.The findings demonstrated that gambogenic acid effectively inhibited melanoma cell proliferation both in vitro study and in vivo mice model.By use of extensive non-coding sequencing of RNA, nuclear-enriched abundant transcript-1 emerged as a key regulator, being up-regulated in melanoma and closely linked to cell proliferation.Manipulating nuclear-enriched abundant transcript-1 levels through cloning experiments confirmed its role.Gambogenic acid treatment decreased nuclearenriched abundant transcript-1 levels, suppressing melanoma cell vitality, ferroptosis, and autophagy.This study underscores GNA's potential as a natural anticancer therapy for melanoma via nuclear-enriched abundant transcript-1 modulation [171].
In the study by Wilking-busch and colleagues, they investigated the expression patterns of Sirtuin proteins in melanoma.The research showed that melanoma has elevated levels of Sirtuin 1 and 2, and that inhibiting SIRT1 has anti-proliferative effects on melanoma cells of human.In A375 melanoma cells, they utilized shRNAmediated interference with RNA to create stable knockdowns in order to investigate the precise functions of Sirtuins 1 and 2. Cellular proliferation and the development of colonies in melanoma cells were decreased under SIRT1 knockdown and the combination of Sirtuin 1 and 2. These findings underscore the substantial influence of Sirtuin 1, particularly in combination with Sirtuin 2, on the growth of melanoma cells, suggesting their potential as therapeutic targets in melanoma treatment [172].
Hong, Ho, and Lee in their study focused on the role of long non-coding RNAs, particularly steroid receptor RNA activator (SRA), in regulating dynamic metastasis in melanoma.Notably, the development of breast and prostate malignancies has been linked to SRA, which encodes the conserved protein SRAP.They examined the effects of SRA on the division, immigration, an invading epithelial-mesenchymal transition, and metastasis of melanoma using RNA interference.Immunofluorescence and PCR analyses revealed measurable SRAP expression in melanoma tissue and B16 melanoma cells.SRA knockdown resulted in significantly decreased proliferation in B16 and A375 cells, along with inhibited B16 cell migration.This suggests that SRA plays a pivotal role in mediating melanoma progression [173].
In the investigation by Shin and colleagues demonstrated the heightened expression of viral protein r-binding protein in melanoma cells, where it phosphorylates histone H2A's threonine-120, inactivating growth-regulatory genes' transcription.Based on H2A T120 phosphorylation, this r-binding viral protein initiates a gene suppression mechanism, in line with its epigenetic function in other forms of cancer.The significance of r-binding viral protein-mediated phosphorylation is underscored by their observation that blocking phosphorylation, induced by r-binding viral protein knockdown or inhibition, mitigates melanoma tumor growth in xenograft models [174].

Nano-sensor for early detection
Nano-sensors are advanced devices intended to identify extracellular vesicles released by cancerous growths, migrating malignant cells, or neoplasm-specific biomarkers.The fundamental parts of them are a transducer, detector, analyte, and sensor.Nano-sensors utilize nanomaterials like nanoparticles, nanowires, nanotubes, or graphene at the nanoscale to track electrical changes in the materials, enhancing early cancer diagnosis and improving long-term patient survival.The choice of nanomaterial depends on factors such as sensing capabilities, compatibility with the target analyte, stability, and ease of fabrication [175].
Wearable sensors have drawn a lot of interest, with many concentrating on electrochemical or optical methods for real-time bodily fluid monitoring, such as sweat and saliva.To improve detection limits and sensitivity for newly discovered biomarkers, these sensors make use of electrochemical biosensors and electro-active substances.In order to improve the end result produced by the sensor, nanomaterials provide a critical role by demonstrating synergistic effects on biological activity, permeation, and enzymatic abilities.Future progress in medical technology, genetic engineering, computational biology, and molecular biology is anticipated to enable the development of highly effective electrochemical biosensors, facilitating tailored treatment strategies for various diseases [176].
Nano-sensors can provide a rapid diagnosis, saving millions of dollars for health systems, while reducing the need for expensive imaging tests using conventional modalities [177].

Nanoparticle-based vaccine platform
Nanoparticle-based vaccines for skin cancer, particularly melanoma, have gained attention as a potential therapeutic approach to harness the immune system against cancer cells.These vaccinations are intended to cure or prevent skin cancer by inducing a tailored immune response against certain antigens produced by cancer cells.Researchers have thoroughly explored nanoparticle-based vaccines, and multiple studies consistently confirm them as a highly promising approach for preventing skin cancer (Table 8).
In a study by Zhao and colleagues, the antitumor efficacy in the B16F10 melanoma cell line is significantly increased by the combination of intravenous administration of the anti-inflammatory triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) and calcium phosphate lipid nanoparticle to administer the tyrosinase-related protein-2 peptide vaccine.This approach effectively remodels the immunosuppressive tumor microenvironment, reducing Treg cells and myeloid-derived suppressor cells while promoting cytotoxic T-lymphocyte infiltration.CDDO-Me also sensitizes tumor cells to apoptosis through Fas signaling (cell membrane receptor).The strategy demonstrates a potent and multifaceted approach to improving vaccine activity against melanoma [178].
Nguyen et al. have created a novel injectable vaccine that combines mesoporous silica NPs (MSNs) and microrods (MSRs) to create dual-scale mesoporous silica.Post-injection, mesoporous silica microrods form a macroporous scaffold, releasing a dendritic cellsrecruiting chemokine, attracting numerous dendritic cells.Mesoporous silica nanoparticles that have been co-loaded with a specific antigen and an agonist of Tolllike receptor-9, then internalize into recruited dendritic cells to produce dendritic cells that are activated to deliver antigen.Additionally, synergizing with an immune checkpoint inhibitor enhances tumor growth inhibition in mice [179].
A cholesterol-conjugated version of resiquimod was developed by S. Kim et al. with the goal of maximizing immunological effectiveness and reducing toxicity.Incorporated into a positively charged liposome TLR7/8 agonist for cancer vaccine therapy, and coadministered with ovalbumin in the B16-OVA model, it efficiently targets secondary lymphoid organs, triggering a potent systemic antitumor immune response with tumor-specific T-cell activation [180].
A novel vaccination including polyinosinic-polycytidylic acid combined with a positively charged poly (sorbitol-co-polyethylenimine) (PSPEI) and tumor lysate protein was created by Rajendrakumar and associates.The corresponding nanocomplexes, known as PSPEI-polyplexed antigen/adjuvant (PAA), were shown to be stable, to have minimal toxicity, and to have enhanced intracellular absorption in dendritic cells, all of which contributed to the maturation of dendritic cells.The PSPEI-PAA nanocomplexes efficiently suppressed tumor development in the B16F10 tumor xenograft system without causing any discernible harm.The study demonstrated enhanced matured dendritic cells, increased CD8 + T-cell infiltration, and heightened cytotoxic T-lymphocyte activity against B16F10 cells [181].
In a subsequent study, Uddin and coworkers prepared a nano-vaccine using a freeze-dry emulsification process, and its impact on transdermal drug delivery, pharmacokinetics, and activation of autoimmune cells in a model of C57BL/6N mice was investigated.By utilizing various biological techniques such as flow cytometry, ELISA, and nuclei and HE staining, the nano-vaccine with an immunomodulator was able to substantially increase transdermal drug delivery and produce strong anticancer immune responses toward B16-OVA melanoma cells without triggering any harm to cells or biological systems.This nanovaccination approach presents a targeted and efficient delivery system for cancer antigens, promoting a stronger immune response compared to conventional aqueous formulations [182].

Personalized medicine with nanotechnology
Customizing treatments for individuals, especially in cancer care, through the use of nanobiotechnology for accurate diagnostics, drug discovery, and delivery is the goal of personalized medicine.This approach improves early detection, minimizes toxicity, and enhances cure rates.The anticipated integration of personalized medicine and nanobiotechnology is foreseen to occur within the next decade, offering the potential for more efficient and precisely targeted treatments, leading to better outcomes for patients [183].
Melanoma therapy has evolved toward precision, refining surgical margins and utilizing targeted small molecules binding to oncoproteins.This approach has significantly improved outcomes, and research is identifying more molecular targets.Notably, a 2015 study report by Beatriz M. Carreno et.Al. showcased personalized cancer medicine by tailoring peptide vaccines to neo-antigens in melanoma tumors, successfully eliciting a diverse T-cell response [184].Another critical advancement is adoptive T-cell therapy, where autologous T-cells are genetically modified to express an artificial T-cell receptor targeting tumor antigens, demonstrating promising potential in cancer treatment [185].
Cytochrome P450 enzymes are crucial in tailoring medicine to individuals due to their influence on drug metabolism.Drug interactions and therapeutic complications for cancer can arise from variations in CYP3A4.Furthermore, inflammation can inhibit CYP3A4, which interferes with the metabolism of nutrients and drugs.In a study, it was noted that psoriasis and melanomas exhibit opposing expression patterns of significant CYP450 and phase II drug metabolizing genes compared to healthy skin, underlining their significance in the context of these diseases [186].
Personalized cSCC diagnosis relies on histopathology, immunohistochemistry, and molecular techniques [187].Skin cancer other than melanoma is becoming more common, necessitating key treatments like surgery and radiotherapy, particularly for older or frail individuals.Personalized high dose rate interventional radiotherapy has demonstrated effectiveness, serving as a viable surgical alternative, especially for elderly individuals or those unfit for surgery [188].
Monitoring therapy and characterizing tumor features are made easier with the use of high-energy ultrasound.Electrical impedance spectroscopy offers high sensitivity but lower specificity in skin malignancy diagnosis.Pigmented lesion assay utilizes genetic information for highly sensitive melanoma detection with moderate-to-high specificity.Raman spectroscopy demonstrates promising accuracy in skin cancer diagnosis.Progress in these diagnostic technologies can pave the way for personalized and optimized skin cancer treatments [189].
In dermatology-oncology research, studies emphasize droplet digital polymerase chain reaction promise for identifying and validating skin cancer biomarkers, vital for p(Dobre & Constantin, 2022)ches [190].

Challenges and remedies in clinical translation of nanomedicine
The clinical translation of nano-formulations for therapeutic intervention of skin cancer involves distinct challenges, with common issues categorized into biological, technological, and study design domains (Fig. 5).Biological challenges encompass hurdles like restricted routes of administration, modulating biodistribution, navigating the passage of NPs through biological barriers, controlling their degradation, and assessing toxicity.Technological hurdles associated with nanoparticles encompass the scale-up synthesis, uniform optimization, and accurate performance predictions.Study design challenges, such as the size, purpose, and timing of nanoparticle therapies, have a substantial impact on clinical studies."Cell and animal designs" are the main focus of many investigations, which may not produce clearly interpreted outcomes in human studies.Consequently, using a singular model proves challenging in mimicking natural reactions within the human body.Overcoming biological barriers, poses challenges in delivering NPs at target sites, necessitating higher drug concentrations with potential suboptimal therapeutic effects.Magnetic NPs show promise in controlled movement, but concerns about their effects on the human body and interactions between magnetic Fig. 5 Illustrates the diverse barriers linked with the clinical translation of various nanoparticles.These barriers encompass biological obstacles (such as administration pathways, distribution within the body, physiological barriers, and adverse effects), technological challenges (including synthesis upscaling, uniform optimization, and predicting performance), and study design hurdles (such as dimensions, purpose, and timing of NP therapies, as well as cellular and animal models).Additionally, it depicts the challenges specific to nanoparticles like SLNs, NLCs, dendrimers, mesoporous silica NPs, iron oxide NPs, and gold NPs fields need thorough research.Despite efforts to enhance biosafety, issues like lung, liver, and kidney damage risk persist due to factors like particle size, shape, and solubility of nanomedicine [191,192].
Clinical translation of inorganic nanoparticles, like gold nanoparticles, encounters challenges such as dose-limiting toxicities, demanding controlled drug release strategies and optimization of surface properties.Iron oxide nanoparticles are limited to treating solid tumors locally.Mesoporous silica nanoparticles confront issues in longterm in vivo fate and kidney clearance due to structural complexities [193].Beside this inorganic nanoparticle faces challenges such as non-biodegradability, susceptibility to protein opsonization due to their large surface area, the necessity for functionalization to assimilate materials, and a propensity for aggregation owing to low solubility.Managing toxicity is a significant concern in their application.Addressing these challenges is vital for safely advancing the effective application of these nanoparticles in medical contexts [194].
Formulating SLN presents challenges including limited drug loading, potential expulsion post-polymeric transition, high water content, unexpected dynamics, and gelation [195,196].Nanostructured Lipid Carriers face hurdles like cytotoxicity, irritative surfactants, suboptimal efficiency for certain drugs, poor control over drug release, and limited loading capacity [197].Addressing these is crucial for refining drug delivery formulations.In clinical translation, understanding toxicology, absorption, biodistribution, and developing triggering modalities are paramount.Alternative strategies for in vivo stabilization are essential for human applications.Tackling these multifaceted challenges is imperative for advancing lipidbased nanocarriers in drug delivery with enhanced safety and efficacy [198].
Unmodified polyamine dendrimers, like polyamidoamine, offer versatile applications, yet their polycationic charges and terminal-NH 2 groups induce liver accumulation, resulting in cell membrane destabilization and healthy cell lysis [199,200].The toxicity, influenced by generation and concentration, poses a challenge to clinical translation, emphasizing the need for strategies to minimize adverse effects for effective biomedical implementation of dendrimeric nanoparticles [201].
A thorough knowledge of in vivo destiny and the influence of cellular interactions on nanoparticle deposition or elimination post-delivery are essential for guaranteeing the prolonged efficacy of medication.One possible remedy is controlled biodegradation of the nanoparticle design.For safety and effectiveness, basic understanding of intracellular processing and nanoparticle-cell interactions must be advanced.Diversifying preclinical models to mirror clinical scenarios, considering genetic profiles and tumor heterogeneity, alongside active targeting strategies, holds promise for succe(Reilly & Pearce, 2019)slation [202].
Ongoing clinical trials for drugs related to skin cancer from ClinicalTrials.govdatabase Numerous ongoing clinical trials are investigating innovative approaches to treat various types of skin cancer.These trials explore novel therapies, targeted drugs, and immunotherapies, aiming to enhance treatment efficacy and patient outcomes.Researchers strive to identify safer and more effective interventions for different skin cancer subtypes through rigorous clinical investigation (Table 9).
The goal of the NCT04657991 clinical study is to evaluate the safety, effectiveness, and tolerability of a combination treatment that includes pembrolizumab, binimetinib, and encorafenib in patients with locally advanced BRAF V600E/K mutation-positive melanoma that has metastasized or is incurable.An open-label safety lead-in phase is carried out before the randomized Phase 3 stage in order to determine the pharmacokinetics and the recommended Phase 3 dosage.There are at least 12 evaluable participants in each of the two encorafenib dose levels that are being examined simultaneously.Following this, 216 eligible patients are randomly assigned 1:1 to either the Triplet Arm at recommended Phase 3 dosage or the Control Arm in a double-blind, randomized Phase 3 phase.AJCC criteria (8th edition)-based stratification is based on disease stage and past systemic adjuvant treatment.
In the adjuvant context, Fianlimab and Cemiplimab are compared to Pembrolizumab to see which is more effective for patients with fully resected high-risk melanoma (NCT01608291), a Phase 3 clinical trial.The main goal is to prove that, in terms of relapse-free survival, Fianlimab + Cemiplimab is better than Pembrolizumab.The purpose of the experiment is to determine if cemiplimab plus Fianlimab works better together to prevent or delay melanoma recurrence following surgical excision.
Two sets of individuals, each at least 18 years old, with significant actinic damage, a minimum of eight actinic keratoses, and a previous diagnosis of a minimum of one non-melanoma skin cancer are enrolled in the clinical study, which has the number NCT04091022.Topical DFMO (difluoromethylornithine) and topical diclofenac will be administered each day to the first group, whereas topical diclofenac and DFMO will be administered as placebos to the second group.A minimum of eight actinic keratoses on the face, neck, scalp, and arms at baseline, as well as a track record of previous squamous or basal cell skin cancer, show that participants are at a higher risk of non-melanoma skin cancer, even if their current condition is otherwise generally good.In comparison to a placebo group, the trial's objective is to evaluate the safety and effectiveness of topical diclofenac with DFMO in lowering the probability of non-melanoma skin cancer in this group at greatest risk.
A Phase II investigation, clinical trial NCT04362722, is assessing intratumoral L19IL2/L19TNF injection in individuals with injectable lesions of cutaneous carcinoma of squamous cells or carcinoma of basal cells.In an estimated amount of 1.0 mL, the study seeks to evaluate the effectiveness of injecting 6.5 Mio IU of L19IL2 and 200 µg of L19TNF, based on positive responses reported in melanoma.This investigation targets high-risk nonmelanoma skin cancer, aiming to broaden therapeutic understanding in this patient group.
Cemiplimab, a PD-1 checkpoint inhibitor, is being tested as a neoadjuvant treatment for high-risk locally recurrent, regionally progressed, and resectable cutaneous squamous cell carcinoma in patients enrolled in clinical trial NCT04315701.This is a Phase II pilot project.The trial assesses how cemiplimab, an immunotherapy, may enhance the body's immune response against the cancer, potentially impeding tumor growth and spread, prior to surgical intervention.
A Phase II randomized research, clinical trial NCT03944941, compares the effectiveness of avelumab alone against avelumab + cetuximab in addressing those suffering from metastatic advanced squamous cell carcinoma of the cutaneous skin.The trial explores whether immunotherapy with monoclonal antibodies, specifically avelumab and cetuximab, can enhance the body's immune response against the cancer, potentially impeding tumor growth and spread throughout the body.
Clinical trial NCT05377905 is a Phase Ib/II study evaluating a novel treatment approach for cutaneous squamous cell carcinoma.The study employs micro-needle arrays containing small doses of doxorubicin, a chemotherapy agent, applied through adhesive-like patches.Aimed at immune-competent or immune-suppressed patients, the research assesses the safety and efficacy of this experimental method.The highest tolerated dose established in a prior study for a different skin cancer informs the dosage selection for this investigation.The study will thoroughly assess the applied skin areas.A further Phase 2 trial (NCT05070403) is looking at the possibility of using afatinib to treat advanced squamous cell carcinoma of the cutaneous skin.The primary goal of this study is to evaluate the effectiveness of afatinib in treating patients with progressive squamous cell carcinoma of the cutaneous skin.
A Phase 2 clinical research, clinical trial NCT04996823, is examining the safety and acceptability of axitinib and ipilimumab combination treatment in individuals with advanced melanoma.The trial is intended primarily for patients who have never had ipilimumab treatment and who are intolerant or resistant to anti-PD-1/PD-L1 therapy.In order to provide important information about this combo regimen's potential as a therapeutic option for advanced melanoma cases that have not responded to conventional anti-PD-1/PD-L1 therapy, the research attempts to assess its risk profile in the designated patient group.Clinical trial NCT04204837 is a Phase II research that evaluates the immunotherapy's Objective Response Rate in patients with cutaneous squamous cell carcinoma that has spread locally or metastatically.Group 1 will receive Nivolumab, while Group 2 will receive a combination of Nivolumab and Relatlimab.Through site evaluations, the study seeks to ascertain the efficacy of these immunotherapeutic protocols applying Response Factors in Solid Tumors Version 1.1 (RECIST1.1).The second group will be observed for a maximum of 5 years following the first dosage.Important information on the effectiveness of various therapies for cutaneous squamous cell carcinoma is provided by this study.
The safety and effectiveness of neoadjuvant atezolizumab in treating patients with high-risk, removed by surgery (resectable) and non-metastatic cutaneous melanoma are being examined in the clinical study NCT04020809.The study focuses on patients that have a high probability of relapse even if they can be surgically removed.By inhibiting programmed cell death-ligand 1 (PD-L1), atezolizumab seeks to strengthen the immune system's capacity to avert melanoma relapse.This trial explores whether atezolizumab, administered before surgery, can improve outcomes for individuals with cutaneous melanoma at higher risk of post-surgical recurrence.

Conclusion
To conclude, this review underscores the multifaceted nature of skin cancer, emphasizing the hurdles posed by its complexity.The present treatment landscape, while offering various therapeutic options, grapples with inherent limitations such as incomplete efficacy and potential adverse effects.In response to these challenges, emerging nanomedicine approaches have garnered attention for their potential to augment treatment strategies.These nanomedicine-based interventions hold promise in optimizing drug delivery, early diagnosis, enabling targeted therapies, and mitigating systemic toxicity.Looking ahead, the integration of nanomedicine into skin cancer therapeutics represents a compelling future direction, poised to revolutionize treatment paradigms and potentially lead to improved outcomes and enhanced quality aspects of life for those individuals grappling from this formidable disease.

Fig. 1
Fig. 1 Represents different challenges in skin cancer treatments that includes biological barriers, late-stage diagnosis, resistance of conventional therapy, high rates of recurrence, adverse effects of chemotherapy

Fig. 2
Fig. 2 Encompasses various therapeutic choices for treating skin cancer including curettage and electrodessication, cryosurgery, photodynamic therapy, immunotherapy, chemotherapy, radiation therapy and targeted drug therapy and Mohs micrographic surgery

Fig. 4
Fig. 4 This circular chart illustrates the distribution of different types of nanoparticles (NPs) studied for skin cancer treatment from 2020 to 2023.It categorizes them into three main groups: Inorganic NPs (gold, silver, zinc oxide, etc.), polymer-based NPs (PLGA, chitosan, PCL), and lipid-based NPs (SLN, liposomes, NLCs).Each category is represented by specific percentages

NLC 5 -
fluorouracil and resveratrol 200-400 nm A431 cell line Increased 5-fluorouracil along with resveratrol retention in the area underlying the layers of dermis and epidermis

Table 1
Summarizes the various chemotherapy medications, their respective side effects on distinct types of cancer, with their prescribed dosage and frequency of administration

Table 2
Summarizes the present therapeutic prospects for skin cancer, outlining their characteristics, constraints, and shortcomings

Table 3
Summarizes the significant potential of inorganic nanoparticles coupled with therapeutic agents across various cell lines and animal models

Table 4
Summarizes the significant potential of polymer-based nanoparticles coupled with therapeutic agents across various cell lines and animal models

Table 5
Summarizes the significant potential of lipid-based nanoparticles coupled with therapeutic agents across various cell lines and animal models

Table 6
Summarize the significant potential of Gold NPs coupled with radiation energy across various cell lines and animal models

Table 7
Summarizes the significant potential of nanogel coupled with therapeutic agents across various cell lines and animal models

Table 8
Summarize the significant potential of nano-vaccine coupled with therapeutic agents across various cell lines and animal models

Table 9
Provide an overview of the treatments and medications that are presently being studied in clinical trials for different forms of skin cancer, as reported in the clinicaltrials.govdatabase