Recent advances and future challenges of nano-based drug delivery systems

: Nanomedicine and nano-delivery systems constitute an emerging and swiftly progressing discipline, employing nanoscale materials for diagnostic tools and targeted, controlled administration of therapeutic agents. Nanotechnology offers substantial advantages for treating chronic ailments, facilitating precise, site-specific delivery of therapeutic agents. Recent applications encompass a diverse array of nanomedicine implementations, including chemotherapeutic, biological, and immunotherapeutic agents, for treating diverse medical conditions. This comprehensive review provides an updated summary of recent strides in the realm of nanomedicines and nano-based drug delivery systems. It critically examines the utilization of nanomaterials to enhance the effectiveness of both novel and established drugs (e.g., natural products) and to enable selective disease diagnosis through the identification of disease marker molecules. The review also addresses the prospects and challenges associated with the transition of nanomedicines from synthetic or natural origins to their practical clinical deployment. Furthermore, the document offers insights into prevailing trends and future prospects within the domain of nanomedicine.


Introduction
Nanotechnology is the deliberate engineering and manipulation of particulate matter into a physical state that is between 1 nm and 100 nm, which may then be reorganized or reassembled into nano-systems with increased function [1] .The potential uses of nanoparticles and nanomaterials in medicine are being investigated more and more.The field of drug delivery stands out as a highly captivating and promising area of application.The nano drug delivery system is one such groundbreaking invention that makes use of nanotechnology to boost treatment efficacy, decrease adverse effects, and improve drug delivery efficiency [2] .A drug delivery system (DDS) is defined as "a formulation or a device that enables the introduction of a therapeutic substance into the body and improves its efficacy and safety by controlling the rate, time, and place of release of drugs in the body" [3] .These systems offer enhanced drug bioavailability by improving drug solubility and stability, thereby maximizing therapeutic efficacy.Their ability to achieve targeted drug delivery to specific tissues, cells, or subcellular compartments minimizes off-target effects and reduces systemic toxicity [4] .
The global market for nano drug delivery is anticipated to reach a remarkable $126.8 billion by 2026, growing at a 14.1% compound annual growth rate (CAGR) between 2021 and 2026, per Grand View Research [5] .The many benefits that nano drug delivery systems provide, such as improved bioavailability, prolonged drug release, targeted administration to particular cells or tissues, and the capacity to overcome biological barriers, may be credited for this exponential expansion [6] .
Nano drug delivery systems help a lot in sustained and controlled drug release, enabling prolonged therapeutic activity, reduced dosing frequency, and improved patient compliance.Overcoming biological barriers, such as the blood-brain barrier, is another noteworthy advantage, as it allows drugs to reach previously inaccessible sites [7] .Additionally, nano drug delivery systems present opportunities for combination therapy, where multiple drugs or therapeutic agents can be encapsulated within a single nanoparticle, promoting synergistic effects and personalized treatment strategies [8] .Overall, the utilization of nano drug delivery systems holds great promise in enhancing therapeutic outcomes, mitigating adverse effects, and advancing the field of precision medicine [9] .
Nano drug delivery systems have both organic and inorganic nanocarriers.Solid liquid nanoparticles, liposomes, dendrimers, polymeric nanoparticles, polymeric micelles, and virus-based nanoparticles are examples of organic nanocarriers.Carbon nanotubes and mesoporous silica nanoparticles are examples of inorganic nanoparticles.For instance, liposomes, a type of nano drug delivery system, have been extensively explored [10] .Doxil, a liposomal formulation of doxorubicin, showed improved efficacy and reduced cardiotoxicity compared to the free drug, leading to its approval for the treatment of ovarian cancer and AIDS-related Kaposi's sarcoma [11] .
Despite their potential, nano drug delivery systems face certain challenges that need to be addressed for their successful translation into clinical applications [12] .The stability and storage of nano drug delivery systems present additional challenges.The complex manufacturing and scale-up processes involved in ensuring consistent quality, reproducibility, and scalability of nanoparticles pose a significant challenge [13] .Establishing standardized guidelines for assessing safety, efficacy, and quality is essential for facilitating regulatory approval and market entry.Lastly, the high cost associated with nano drug delivery systems limits their widespread adoption.Developing cost-effective manufacturing processes and addressing economic feasibility are necessary to improve accessibility [14] .

Types of the NDDSs
Liposomes, dendrimers, carbon nanomaterials, fullerenes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers, nano shells, quantum dots, superparamagnetic nanoparticles, and others are examples of the many morphologies of nanoparticles [15] .The description, importance, and challenges of these different morphologies of nanoparticles as drug delivery systems are given below:

Lipsomes
Liposomes are colloidal particles enclosed by lipid bilayers, formed by self-assembly of amphiphilic phospholipids.They have sizes ranging from 25 nm to 200 nm and are often used in drug delivery, particularly targeting cancer cells.Liposomes were discovered in 1965 and have been utilized as drug delivery systems since 1971 [16] .The hydrophobic effect drives their bilayer structure formation.Liposomes can evade opsonization by the reticuloendothelial system when PEG is added to their surface.Doxil, a liposomal medication, was the first FDA-approved nanotechnology product for cancer treatment.Liposomes have the advantage of delivering both biological macromolecules like DNA and smaller molecules [17] .

Types of liposomes
Liposomes are widely used in pharmaceutical and cosmetic industries as carriers for drug delivery.They offer advantages such as membrane-like structure, drug stability, improved biodistribution, and compatibility with hydrophilic and hydrophobic drugs [18] .There are four categories for liposomes: 1) Traditional liposomes are composed of an aqueous core and a lipid bilayer that may contain neutral, cationic, or anionic cholesterol and phospholipids.In this case, the lipid bilayer and the aqueous space can be filled with either hydrophobic or hydrophilic substances.2) PEGylated types: The surface of the liposome is coated with polyethylene glycol (PEG) to create steric equilibrium.3) Ligand-targeted type: Ligands are connected to the surface of the liposome or to the end of PEG chains that have previously been attached.Ligands include peptides, sugars, and antibodies.4) The fourth liposome type is known as a theragnostic liposome and incorporates the first three liposome types.It frequently contains a nanoparticle as well as a therapeutic, imaging, and targeting component [19] .
The normal production process includes thin layer hydration, mechanical agitation, solvent evaporation, solvent injection, and surfactant solubilization [20] .

Liposome as drug delivery systems
Due to their exceptional qualities, liposomes have been widely researched for their use in medicine delivery to malignant and tumor tissues using two main methods: passive targeting and active targeting as shown in Figure 1 [21] .Liposomes can be surface functionalized to dedicate stealth through PEGylation and to meliorate receptor mediated endocytosis by utilizing targeting ligands such as antibodies, peptides, proteins, carbohydrates, Aptamer, and various other small molecules.PEGylation prolongs liposomal circulation half-life in vivo.Types of drugs based on whether they are hydrophobic or hydrophilic can be encapsulated into the aqueous lumen, incorporated into the lipid bilayer, or conjugated to the liposome surface [22] .
Passive targeting is based on the physical features of the tumor and the magnitude of the nanomaterials.Cancer cells overexpress vascular endothelial growth factor (VEGF), which causes an excessive amount of angiogenesis.The proper size of liposomes may flow in the bloodstream for a longer duration, allowing the anti-tumor drug nano system to concentrate on the tumor tissue.Tumor tissue has bigger vascular holes than normal ones [23] .
When a drug delivery system accesses malignant tissue, nanoparticle retention durations rise due to anomalies in the lymphatic system, which is not conceivable for tiny drug molecule [24] .This process involves further coating the nanoparticle with a biocompatible PEG polymer, which allows it to escape the reticuloendothelial (RES) system as well as prolongs the duration blood circulates in the circulatory system; PEG has this effect by shielding lipsomes from opsonization [25] .
In photodynamic treatment (PDT), light is used to activate photosensitizing drugs, producing reactive oxygen species (ROS) or singlet oxygen which destroy tumors.PDT was first employed for bladder cancer and has since been researched for usage in other cancers [26] .By encapsulating photosensitizers, nanocarriers can increase PDT by increasing the bioavailability and stability of the photosensitizers.However, due to the limited light penetration, PDT is only effective on surface tumors.Limitations such as low bioavailability, hydrophobic adverse effects, high dosage requirements, and self-aggregation in aqueous media are addressed by nanocarriers.They show promise for raising PDT effectiveness [27] .
Liposomes are versatile carriers for drugs, being able to transport both water and lipid-soluble drugs due to their amphiphilic and non-ionic structure [28] .Researchers can manipulate their permeability, stiffness, size, and surface functionalization to create sustained and targeted drug delivery systems [29] .Liposomal delivery addresses the need for biodegradable drug delivery and prevents drug oxidation [30] .
Despite their benefits, liposome-based structures have drawbacks that prevent widespread clinical application.Their physical and chemical stability, low solubility in aqueous solutions, short half-life in the body, high production costs, and allergic reactions to specific liposomal chemicals are the key challenges [31] .

Carbon nanomaterials
DNA's basic building block, carbon, is responsible for the creation of all life on earth.Due to its unique electron configuration (1s 2 , 2s 2 , 2p), it can be found in a variety of forms [32] .Due to its capacity to bind itself and practically all elements, it has a wide range of technical uses, including the transport of pharmaceuticals and synthetic materials [33] .
CBNs are divided into carbon nanotubes, graphene, mesoporous carbon, nanodiamonds, and fullerenes based on their structural differences.These materials have enhanced drug-loading capacity, biocompatibility, and immunogenicity [34] .It has been possible to create biocompatible scaffolds and nanomedicines using functionalized CBNs.Due to their superior supramolecular stacking, high adsorption capacity, and photothermal conversion capacity, they have been investigated for cancer therapy [35] .Therapy can be improved by combining chemical functionalization with adaptive characteristics.

Carbon nanotubes
Carbon nanotubes (CNTs) are tubes or cylinders with a special blend of stiffness, elasticity, and strength.Single-walled nanotubes (SWCNTs) are elongated enfolded graphene sheets that were created through sp 2 hybridization and have one-dimensional hollow and cylindrical forms.These CNTs have a diameter of roughly 1 nm and can grow to hundreds of times their original length [36] .
Multi-walled carbon nanotubes (MWCNTs) are composed of many graphene sheet layers and have more complicated electrical properties.Sizes of this type of nanotubes range from 5 nm to 50 nm [37] .
Functionalized CNTs (f-CNTs) have improved solubility, biocompatibility, and reduced toxicity when tagged with functional groups or therapeutic molecules [38] .Covalent and non-covalent modifications are used to alter CNT surfaces, but they may affect mechanical strength [39] .
The potential benefits of SWCNTs in metal nanoparticles, such as bulk medication loading, structural adaptability, inherent stability, enhanced circulation time, and bioavailability, have drawn attention among the many types of carbon nanotubes [40] .Higher drug loading is possible thanks to the ability of functionalized SWCNTs to entrap low molecular weight substances and antibodies.This also enables the conjugation of biological molecules without inducing an immunological response.Doxorubicin (DOX) is commonly used in chemotherapy, but it has limitations, including side effects, low barrier crossing ability, and irreversible toxicity.Carbon nanotubes (CNTs) can effectively transport DOX, reducing side effects due to their high surface area, stability, and cell membrane penetration.In breast cancer treatment, amino-functionalized single-walled CNTs (NH2-SWCNTs) combined with hyaluronic acid (HA) showed faster DOX release in the tumor cell environment.SWCNTs-DOX-HA reduced tumor cell growth and induced apoptosis more effectively than SWCNTs-DOX alone, enhancing breast cancer treatment and the structure of doxorubicin (DOX) is shown in Figure 2 [41] .pH-responsive SWCNT-folic acid (FA) conjugates demonstrated higher drug loading and antitumor effects, reducing DOX side effects.FA-EDA-MWCNTs-DOX showed pH-dependent release and cytotoxicity against breast cancer cells [42] .

Graphene
Graphene, a single layer of carbon with partially filled sp 2 -orbits, possesses large surface area, superior thermal conductivity, optical clarity, and strong mechanical strength.It acts as a semiconductor, forming new quasi-particles upon interaction with electrons.Quantum dots and graphene nanoribbons enable ballistic transport without scattering [43] .
Graphene exhibits good electrical conductivity and reduced solubility.Sol-gel chemistry allows for alterations like graphene oxide and layered graphene-oxide.Graphene and its derivatives have diverse applications in medicine and drug delivery, with polymer surface modification enhancing biocompatibility [44] .Graphene nanomaterials respond to stimuli, regulating drug release based on internal and environmental inputs, improving absorption, overcoming barriers, and minimizing side effects [45] .
Because of the functional groups that are present on the side walls, GOs have attracted a lot of attention among graphene nanomaterials.DOX and camptothecin were captured by graphene through hydrophobic interaction and π-π stacking.The presence of hydroxyl and carboxyl groups on the surface of GOs makes it easier for them to attach to the hydroxyl and amino groups of DOX [46] .
A study using the 4T1 cancer cell lines showed that the electrochemical method successfully exhibited carrier capacity and cellular capacity.Based on pH-stimuli drug delivery, 5-fluorouracil loaded GO was created and the structure of 5-fluorouracil is shown in Figure 3 [47] .This formulation controlled the release of the anticancer agent in the tumors environment's acidic pH of 5.8, however the release was dramatically reduced in the physiological pH of 7.4.

Multifunctional nanoparticles as NDDSs
As a result of their direct targeting of the damaged organs, metal nanoparticles allow drug delivery systems to minimize adverse effects.

Silver nanoparticles
The manufacture of NPs and nanoparticles uses silver, which is the precious metal with the highest profit-orientedness because of its antiviral, antifungal, and antioxidant properties.These are wellknown due to their unusually improved physicochemical properties relative to the bulk material, such as optical, thermal, electrical, and catalytic capabilities, as well as their anti-bacterial, anti-viral, antifungal, and antioxidant activities [48] .A variety of different cell types have been shown to be susceptible to cytotoxicity caused by silver nanoparticles via apoptosis and necrosis.Additionally, they show results against side effects of conventional therapies such DNA damage, the production of reactive oxygen species (ROS), an increase in lactate dehydrogenase (LDH) leakage, and inhibition of stem cell differentiation [49] .

Gold nanoparticles
AuNPs, also known as gold nanoparticles, are potent radiosensitizers used in medical operations such drug administration and cancer treatment [50] .Gold nanoparticles, or AuNPs, are potent radiosensitizers utilized in cancer treatment and drug administration.Au NPs are able to deliver a variety of pharmaceutical compounds, recombinant proteins, vaccines, or nucleotides into their targets thanks to their capacity to govern drug release via internal biological triggers or external light activation.Given its impressive effectiveness, AuNP-based drug delivery has drawn a lot of attention [51] .

Targeting strategy of the NDDSs
There are two mechanisms by which nanocarriers can deliver to target nano-drugs: active targeting and passive targeting.In active targeting, we focus on specific markers found only in sick cells, not healthy ones.For example, we can use molecules that interact with the overexpressed folate receptors in sick cells.CA-125 is an example of a biomarker overexpressed in ovarian cancer that can be actively targeted [52] .
In passive targeting, the size of polymers is important.Larger polymers can accumulate more at the site of diseased cells.This happens because the polymers can pass through leaky blood vessel junctions and reach the sick area.It's like taking advantage of the openings in the blood vessels to deliver the drugs where they are needed [53] .
In Figure 4, the illustration of passive and active targeting of nanoparticles (NPs) for enhancing the therapeutic efficacy of anticancer drugs Figure 4A: passive targeting of NPs taking advantage of the enhanced permeability and retention (EPR) effect; Figure 4B: active targeting of NPs attached with ligands to enhance accumulation and cellular uptake of NPs via receptor-facilitated endocytosis [54] .

Application of NDDSs
Nano drug delivery systems have various applications in medical field.Some are given below:

AuNPs in cancer therapy
For gold nanoparticles to be used as therapeutics, it is essential to comprehend how they are biodistributed and accumulate in living systems.This can only be done with accurate characterization of the nanomaterials, a reliable animal model, a sizeable sample, and strong statistical analyses.AuNPs regulate damage to healthy cells and lessen the likelihood of adverse outcomes [55] .AuNPs are a novel component in cancer therapy that display aggregation [56] and a size-dependent lethal effect on various cancer cells [57] .The anti-cancer action of AuNP is complicated and poorly understood.The positive charges are on AuNPs, but cancerous and healthy cell membranes include molecules that are negatively charged, such as lipids, which cause AuNPs to be absorbed and internalized [58] .Another mechanism by which AuNPs enter cells is endocytosis, which results in the accumulation of tiny AuNPs inside HeLa cells [59] .We focused on the development of the following gold nanoparticles-based drug delivery systems: AuNPs covered by PEG carrying carboxylic groups, PEG-AuNPs linked to DOX, PEG-AuNPs linked to BLM, and, finally PEG-AuNPs linked to both DOX and BLM (referred to as S1, S2, S3 and S4, correspondingly) as illustrated in Figure 5 [59] .

AgNPs as anti-viral agents
A significant problem for the pharmaceutical, medical, and biotechnological industries is the development of resistance by different viral pathogens against anti-viral drugs [60] .Because of their successful interactions with sulfhydra, amino, carboxyl, phosphate, and imidazole groups, AgNPs are well acknowledged to suppress viruses.Due to their inhibitory efficiency against a variety of viruses, including hepatitis, coronavirus, influenza, herpes, recombinant respiratory syncytial virus, and human immunodeficiency virus, AgNPs have recently gained popularity as anti-viral medicines [61] .AgNPs were employed to create a nanoscale delivery system for the antiviral drug zanamivir, and surface-enriching AgNPs with amantadine to prevent H1N1 virus resistance as demonstrated in Figure 6 [62] .

Conclusion and future perspectives
Incomparable opportunities to develop medical diagnoses and treatments for human ailments have been made possible by the development and growth of nanotechnology for therapeutic and medicalrelated purposes over the previous two to three decades.As shown by their enhanced solubility of a variety of cargoes, disease-fighting capacity, controlled transmission, improved strength, increased biodistribution inside the organism, Modula table (adjust to certain proportion) means of transport across tissues and cells, and controlled delivery to the target location, the nanomaterials exhibit a high degree of control over the desired properties.These kinds of methods are available to make detectors and imaging components that have improved identification and analysis sensitivity.Before this research can offer clinically effective medicines, there are still many challenges to be solved.The development and testing of cutting-edge methods for controlling how nanoparticles interact with the body is one of the main challenges to turn this technology into medicines.It is necessary to find a solution to the problem of delivering nanomaterials to specific body regions while preventing entrapment by organs like the liver and spleen.By modifying material qualities at the nanoscale, there has been enough room to improve and change current technologies.Therefore, with enough time and research, the promise of nanotechnology-based drugs may become a reality.

Figure 4 .
Figure 4. Passive and active targeting of nanoparticles (NPs) as a drug delivery system.

Figure 5 .
Figure 5. Synthesis of PEG-AuNPs NPs (a) the chemical composition of DOX and BLM and the procedures involved in conjugating them to the surface of S1; (b) a schematic depicting the production of S2, S3, and S4 NPs.

Figure 6 .
Figure 6.The reversal of H1N1 influenza virus-induced apoptosis by silver nanoparticles.