Cubosomes: evolving platform for intranasal drug delivery of neurotherapeutics

Background As per World Health Organization (WHO) database, neurological and psychiatric disorders constitute a significant and escalating source of morbidity, impacting over one billion lives with a staggering 9 million fatalities. Unfortunately, the magnitude of these disorders remains largely untreated, primarily due to the formidable challenge of the cerebrospinal fluid–brain barrier (CBB), blood–brain barrier (BBB), as well as the blood–cerebrospinal fluid bar‑ rier (BCSFB) compromising the central nervous system (CNS) therapies. Thus, there is a need to explore innovative drug delivery platforms capable of overcoming these barriers in order to facilitate effective delivery of therapeutic drugs. Main body of abstract Intranasal drug delivery (INDD) of nanoformulations has emerged as a promising approach, leveraging advantages such as a high surface area, nanoscale particle size, mucoadhesion, noninvasive administration with rapid, and greater drug bioavailability. In this, cubosomal drug delivery (DD) has emerged as a pivotal targeted drug delivery strategy, particularly in the therapy of neurological ailments. Nowadays, researchers and academicians have focused their efforts to tailor cubosomes (CBS) specifically for improving efficacy of central nervous system (CNS) therapies. Conclusion This review gives an idea about current status of neurological disorders (ND), the barriers that restricts CNS drug delivery (BBB), and possible nasal pathways of CBS for effective drug transport. A central focus is placed on intranasal (IN) cubosomal formulations for several NDs, elucidating their potential benefits while addressing exist‑ ing challenges. In essence, this comprehensive review provides valuable insights into innovative approaches that hold promise for addressing the use and need of IN‑CBS in the treatment of NDs.


Background
Understanding the prognosis of neurological ailments like Parkinson's disease (PD), Alzheimer's disease (AD), and similar central nervous system (CNS) disorders has always been more challenging than the prognosis of other critical ailments diseases [1][2][3].Despite enormous efforts to intervene and design CNS medications for novel and effective therapies, more than 90% of newly proposed pharmacological entities have failed to get clinical approval from the US Food and Drug Administration (FDA) [4].According to the World Federation of Neurology, neurological disorders (ND) affect one billion individuals worldwide [5], with the number expected to climb in the coming years.Therapies and clinical monitoring for ND are exorbitant [6].Existing diverse biochemical, physiological and metabolic barriers that collectively compose the bloodbrain barrier (BBB) limits drug access into the CNS region, posing a significant challenge in the expansion of CNS therapeutics [7].Furthermore, non-targeted administration of therapeutic medications or diagnostics may induce considerable impairment to glial cells or neurons.As a result, innovative drug delivery platforms for therapeutic medications in the treatment of neurological illnesses are the most sought-after strategies [8].Since few decades, intranasal drug delivery (INDD) is gaining popularity as a noninvasive method for CNS medicines and a reliable alternative to oral and parenteral routes [9].The nasal mucosa has emerged as a potential location for efficient delivery of CNS medication.It has various advantages over the oral route, including high blood flow, wide surface area, avoidance of systemic side effects, avoids hepatic first pass metabolism, a porous endothelium membrane, and easy accessibility [10][11][12].A plethora of active moieties can be administered intranasally to obtain the desirable CNS effect [13].Intranasal CBS are a viable route for medication administration to the CNS, especially in the context of treating major ND.These colloidal nanoparticles have a distinct liquid crystalline cubic phase structure.They are made up of lipids and water, known for better drug delivery owing to their exceptional properties [14,15].Furthermore, modifying CBS with various ligands, polymers, or surfactants improves their stability, mucoadhesion along with medication interaction across the nasal mucosa.
This review briefly examines current ND statistics, describes the nature of the BBB, and reflects into the nasal anatomy.A thorough analysis of nose-to-brain (NTB) drug transport mechanisms in CBS is presented in this review.Briefly, this session reviews the suitability of CBS platforms for NTB delivery while addressing current obstacles, and providing insights into future possibilities.

Current status on neurological disorders
At present, neurological disorders (ND) pose the second biggest cause of disability and death globally.As reflected in World Federation of Neurology database [16], ND affects around 40% of the global population and is expected to nearly treble by 2050.Approximately 80% global population lives in low-and middle-income nations, which accounts for over 90% neurological disabilities and 84% fatalities.Thus, in line with WHO's Intersectoral Global Action Plan (IGAP) on ND, a comprehensive, coordinated response across numerous sectors is required to increase access to ND treatment [17].
Currently, ten disorders account for approximately 90% of the total neurological disability-adjusted life years (DALYs): (i) stroke, (ii) neonatal encephalopathy, (iii) migraine, (iv) dementia, (v) meningitis, (vi) epilepsy, (vii) neurological problems from premature birth, (viii) nervous system cancers, (ix) autism spectrum disorder and (x) Parkinson's disease [16].It is predicted that by 2050, the stroke fatalities in persons aged 60 years or elder are expected to elevate to 8•8 million, mostly due to aging and associated related complications [18].Similar findings were reported in the Lancet Medical Journal in collaboration with the Indian Council of Medical Research (ICMR) [19].Epilepsy can develop in patients with history of neonatal trauma, brain injury or brain infections.In 2022, over 65 million (15%, Fig. 1) persons worldwide suffered from epilepsy, making it one of the most burdensome neurological disorders.The 2022 predictions have cited existence of more than 55 million Alzheimer's patients [20].In comparison, 2.8 million people are affected with multiple sclerosis [21].Migraines are a common type of headache that can cause severe, pulsating pain.According to the Migraine Research Foundation, it affects over 39 million Americans, with women three times more likely than men to get migraines.Migraines afflict one in every seven people worldwide.Chronic migraines affect up to 148 million people around the world [22].An estimated 34-64% of migraine sufferers are reported to have a family history of similar ailments.Inherited genetic variants in CACNA1A, ATP1A2, and SCN1A have direct correlation with the risk of migraines, with many more genetic mutations still being studied [23].A primary brain or spinal cord tumor is the one that originates in the brain or spine.In 2020, the global incidence rate reported for brain and other CNS tumors was 3.5 per 100,000 people.The male incidence rate (3.9 per 100,000) was more than the female incidence rate (3.0 per 100,000).Also, highincome nations had greater incidence rates than middleincome and low-income nations [24].According to the International Association of Cancer Registries (IARC), more than 28,000 people suffering from brain tumors are reported in India annually with over 80% of them succumbing to death [25].
This health threat calls for the development of novel neurotherapies, motivating continuous research.According to reports, the cost of ND treatments is burdensome [20].According to the analysis, the global gross neuroscience market (GNM) was valued $612 billion in 2022 and is expected to expand to $721 billion by 2026, with cumulative compound annual growth rate (CAGR) of 4.2% across categories [26].Comprehending the severity of ND, neurology is one of the most important areas for clinical studies.According to the Pharma R&D Annual Review, neurology will be the third key area of focus for clinical trials in 2021.India's Neurology Clinical Trials market is expected to increase from $95.1 million in 2022 to $182.7 million by 2030, with a CAGR of 8.5% between 2022 and 2030.In November 2022, Hyderabad-based Suven Life Sciences announced that the first patient has been randomized in the global phase III clinical trial of its medicine Masupirdine used to treat agitation in Alzheimer's patients [27].Teva Pharmaceutical Industries, Biogen Idec, and other businesses are also conducting trials, primarily for illnesses such as multiple sclerosis and Alzheimer's disease.A study related to the impact of glutathione (GSH) supplementation in mild cognitive impairment (MCI) patients was recently added to the Clinical Trials Registry-India (CTRI), approved by the Drugs Controller General of India (DCGI) and Department of Biotechnology (DBT) [28].In June 2021, the FDA sanctioned regulatory clearance to aducanumab, the first-in-class active for Alzheimer's therapy.Aducanumab was developed in collaboration between Biogen and Eisai [29] which demonstrated potential therapeutic benefit to patients in terms of the ability to reduce amyloid plaques [30].However, there is no sufficient evidence to support the linkage of amyloid plaque destruction with improved cognitive performance as a result of aducanumab's effect.In 2022, a study associating amyloid plaques to cognitive deterioration called into question the reasoning for approving aducanumab [31,32].Aducanumab's price in the USA dropped by 50% and was recommended for only critical patients participating in the clinical trials [33].Despite aducanumab's favorable profile and the potential to improve care for Alzheimer's patients, this case demonstrates the intricacies in the clinical translation of neurotherapeutic entities.

The challenge of blood-brain barrier (BBB)
The BBB poses a substantial obstacle for drug of active molecules to the brain.The blood-brain barrier is composed of astrocytes, pericytes as well as endothelial cells which make blood-brain capillaries [34][35][36].This enables the BBB to maintain homeostasis by regulating molecular movement in and out of the CNS while preventing the entry of plasma components, blood cells, or viruses [37].This multicellular complex is so densely packed that chemicals are transported into the brain via either transcellular, passive diffusion or active targeting.Efflux transporters like breast cancer resistant protein (BCRP), P-glycoprotein (P-gp), as well as multidrug resistanceassociated protein (MRPs) expressed on the luminal membrane of BBB-specific endothelial cells serve as molecular pumps for brain to the blood passage [38,39].Organic anion transporting polypeptides (OATP) [45], glucose transporter 1 (GLUT1), and l-Type Amino Acid Transporter 1 (LAT1) are uptake transporters expressed in the BBB, aid in transferring the endogenous substrates to brain.Finally, drug-metabolizing enzymes such as cytochrome (CYP) 450 enzymes within brain endothelial cells lead to the formation of the metabolic barrier [40,41].
Latest 3D models aim toward removing the loopholes during scale-up translation.Organ-on-a-chip (OOAC) technology, also known as emergent BBB organoids, has been extensively studied for BBB research [42].In addition, in vivo rodent experiments are employed right from the drug discovery to evaluation across BBB.As previously stated, the BBB is the primary barrier in the effective brain delivery of therapeutic actives that compromises the therapeutic efficacy for a range of ND.Chu et al. described a strategy for opening the BBB in mice using intra-arterial injections of hyperosmotic mannitol guided by magnetic resonance imaging (MRI).The process gives real-time feedback to control where the BBB gate opens, letting materials to enter across regions from which they are typically excluded [43].Nanoformulations such as CBS aid in delivering integrated cargos to the brain across the BBB.Tween 80 stabilized cubosomes have demonstrated a viable mechanism for drug delivery across the BBB [44].Elsenosy et al. had synthesized duloxetine HCl CBS to increase brain bioavailability of duloxetine HCl by bridging the BBB components [45].

Comprehensive exploration of nasal anatomy
The nasal interior components comprise of two huge irregular cavities.Each hollow extends beneath the palate.The roof is made up of the ethmoid scratch plate located at the base of the skull [46].The septum divides the two nasal cavities.Three (or four) turbinates, or conchae, form a matching canal, or meatus, and are convoluted into the outer wall.The superior turbinate is positioned in the cavity's top and posterior parts.It is the smallest turbinate, while the inferior and middle turbinates become larger [47].Surface area of both nasal cavities in an adult is around 160 cm 2 with 15 mL volume capacity [48].The nasal cavity serves several functions, including olfaction, dust and particle removal, and heating and humidifying the air for breathing.The nasal cavity constitutes four areas: vestibule, respiratory, olfactory as well as nasopharynx-associated lymphatic tissue (NALT).The respiratory and olfactory areas, located in the nasal cavity's center are critical for INDD.The respiratory region is the largest and most vascularized area of the nasal cavity that provides optimal site for systemic drug absorption after nasal delivery [49,50].The olfactory region with an area ranging from 2 to 12.5 cm 2 forms less than 10% of the nasal cavity's surface area [51].Since it is located in the highest cavity, it is difficult for drugs to reach at the site of action [52].Olfactory sensory neurons (OSNs) in the olfactory area act as site wherein CNS has direct touch with the body's environment, explicitly the nasal membrane.This opens up the prospect of directly delivering drugs to the brain via noninvasive route [48].NALT as a component of immune system aids to prevent infection in the posterior cavity.Intranasal vaccines, such as the swine flu or seasonal flu vaccines rely heavily on T-cell immunity [53,54].

Pathways of drug transport via nasal cavity to the brain
Nasal to brain (NTB) channels offers a noninvasive medication delivery mechanism [55].Both olfactory and respiratory areas of nasal cavity are directly linked to brain tissues via olfactory neurons and trigeminal nerves.Nonetheless, NTB medication transport to the CNS is predominantly reliant on the olfactory area.Allied mechanisms are either paracellular or extracellular diffusion along with intracellular absorption into olfactory neurons [50].Furthermore, transcellular techniques such as endocytosis, simple diffusion as well as paracellular approaches via cell junctions provide additional pathways for drug transport across olfactory epithelium [56].In contrast, the respiratory area also serves as a location of indirect drug transport which involves a counter current interchange of actives in the bloodstream with subsequent delivery of significant quantities to the BBB [57].
Drug deposition and absorption occurs in three zones of nose cavity: olfactory, respiratory and vestibule.The olfactory zone is essential in drug targeting to the CNS and CSF (cerebrospinal fluid) via its epithelium.The olfactory zone is difficult to access since it is located in the upper nasal cavity: below the superior turbinate and cribriform plate.The olfactory epithelium consists of neuronal cells from the CNS's olfactory bulb and migrate across the cribriform plate pores before reaching the olfactory epithelium [56].This olfactory area also has the trigeminal nerve.Both, the olfactory epithelium as well as the trigeminal nerve serve as direct routes for nose-to-brain delivery (Fig. 2A) [52].Trigeminal nerve is principally responsible for pain and temperature perception in the respiratory system.Three branches of trigeminal nerve link to the brain stem and olfactory bulb [58,59].As a result, medication delivery via trigeminal nerve can be achieved directly from nose to the brain (Fig. 2B).Majority of the trigeminal nerves exists in the respiratory zone while few of them are located in the olfactory area [60].Furthermore, the respiratory zone with densely packed capillaries occupies most of the nasal cavity [53].As a result, medication supplied to the respiratory system gets absorbed into the bloodstream and circulates across the body, setting up an indirect conduit for targeted delivery to the brain.So, the medications reaching the trigeminal nerves would thereby directly to the brain.Furthermore, those medicines that do not retain in the nasal cavity and instead traverse across the airways or esophagus may reach the brain via systemic circulation.However, owing to the thickness of the BBB and substantial drug processing and/or removal in the body, the amount of medications reaching brain via systemic circulation is likely to be significantly lower than the nose-to-brain delivery [61].
The olfactory route (A), the respiratory route (B), as major pathways for nose-to-brain drug delivery.

Nasal-brain lymphatic system
Lymphatic system connecting the nasal cavity and brain plays a vital role in defining the drug uptake in case of therapies for intractable brain as well as nervous system disorders.Noninvasive, nasal route would be especially useful in delivering genes and peptide drugs to the CSF and brain parenchyma with challenges of BBB and the associated limited transport from the blood vessels to the brain parenchyma post-oral or intravenous administration [62].Intranasally given medicines can be transported to the CSF relatively with an ease via the olfactory/nasal lymphatic pathway due to CNS fluid dynamics (including CSF-ISF exchange).There onwards, they can be successfully disseminated to brain tissues or other neurological milieu.This pathway is reported to bypass the BBB's constraints and maintain therapeutic concentrations in the brain while preventing or minimizing peripheral side effects arising from the brain targeting of the drugs [63].The nasopharyngeal region, located posterior to the nasal cavity, contains NALT, the lymphatic system.Mucosaassociated lymphoid tissue (MALT) contains NALT, which eventually leads to cervical lymph nodes.As a result, medications can be either transported to the brain directly via the brain lymphatics or via the body's circulation indirectly.NALT may be effective at delivering submicron formulations to lymph nodes [64].

Exploring cubosomes as carriers for brain targeting
Numerous cubosomes (CBS) as drug carriers are studied as depicted in various literature and research databases.In one work, CBS transport was carried out by receptormediated endocytosis in the presence of these transporters, particularly low-density lipoprotein (LDL) receptors, utilizing the hCMEC/D3 cell line [44].According to another publication, researchers prepared duloxetine HCl (DLX) CBS gel for brain targeting via IN channel.Based on brain efficiency studies, the author attributed increased DLX penetration from the cubosomal gel to the brain via olfactory route and even, across the BBB succeeding systemic absorption [45].Another study indicated that cubosomal in situ gel IN had considerably greater (p < 0.001) AUC 0-inf in the brain than resveratrol (RSV) solution (oral) and RSV solution (oral).This demonstrates that drug absorption into the brain from the nasal mucosa occurs primarily through the systemic and olfactory pathways, with drug release via passive diffusion [65,66].Odorranalectin (OL) may also stimulate or promote the extracellular [67], active transport of CBS across the olfactory mucosa.On the other hand, OL fabrication may permit direct passage of CBS to targeted regions of brain via trigeminal neurons [68,69].

Cubosomes
The following sections deals with the properties, advantages of CBS over other nanocarrier system and components used for formulation along with different preparation techniques of CBS.

Characteristics of cubosomes
Colloidal dispersions of non-lamellar lyotropic crystalline phases were termed as "cubosomes" by Landh and Larsson.CBS are biocompatible drug delivery carriers composed of liquid, crystalline, nanosized particles grafted with particular amphiphilic lipids in varying ratios [70][71][72].They are transparent, isotropic, non-toxic and biodegradable cubic liquid crystals that remain stable in surplus of water physically.The addition of polymers to CBS colloidal dispersions can help them to achieve thermodynamic stability.CBS can control the delivery of actives via as diffusion across the cubic phase's regular channel [73,74].CBS produce aqueous surfactant systems at high amphiphilic concentrations with relative molecular alignment and distinct geometrical symmetry [75].

Advantages of cubosomes (CBS)
Cubosomes (CBS) have been found to be a potential therapeutic nanocarrier in recent years due to their biocompatibility, capacity to co-encapsulate hydrophilic, hydrophobic, even amphiphilicity as well as stability in the biological milieu with improved cell internalization.Vast inner surface area imparts higher drug-loading capability while distinctive inner self-assembled cubic membrane morphology provides improved drug encapsulation with regulated release profiles: critical parameters for brain delivery [76].Thus, CBS are reported to be beneficial for ophthalmic, oral, transdermal as well as smart chemotherapeutic drug delivery applications [77].Particularly, the highly structured internal structures of CBS [78] impart viscosity which subsequently reflects in effective uptake of therapeutic molecules with sustained release profiles and better physical stability.Thus, CBS approach may illustrate as a better lipid-based drug delivery methods for in vivo applications [79].

Amphiphilic lipids Glycerol monooleate (GMO)
GMO, a monoolein (MO), is a GRAS and FDA-approved amphiphilic lipid, frequently utilized in the production of CBS.GMO is a polar, unsaturated monoglyceride, known to self-assemble in water to create bicontinuous, cubic structures [80,81].GMO's possess amphiphilic chemical structure, a hydrophobic tail containing polymeric chains as well as hydrophilic, polar (groups) head of hydroxyl functionality.Both these functionalities are known to form H-bonds with water.GMOs are designated as GRAS (generally regarded as safe) since they are biodegradable, biocompatible, and have low toxicity.Ahirrao et al. developed a GMO-based CBS for transnasal delivery of polyphenolic resveratrol (RSV) to the brain [69].Crystalline, lyotropic nanoparticles were created to co-deliver the chemotherapeutic moiety of pemetrexed (PMX) with resveratrol (RSV) for better therapeutic outcomes during lung cancer therapy.In vivo investigations in mice with urethane-induced lung cancer showed that these lyotropic nanoparticles are capable of arresting tumor growth by blocking angiogenesis and causing apoptosis [82].

Stabilizers
Stabilizers play vital role in development of CBS in terms of stability by preventing the coalescence (or its recurrence) of scattered particles on extreme dilution [90].In this case, the stabilizer works like an electric barrier across the lipid-water interface without disturbing the crystallinity of the cubic liquid.Pluronic F127 is a watersoluble triblock copolymer, non-ionic surfactant, primarily made of polyethylene oxide (PEO) and polypropylene (PPO) configured as PEO-PPO-PEO, with hydrophobic PPO as well as hydrophilic PEO segments.Steric stabilizing impact of pluronic F127 in CBS is attributed to the surface adsorption of hydrophobic PPO onto the along with the external protrusion of hydrophilic PEO segment on exposure to aqueous environment effect [81].

CBS fabrication techniques for INDDS
In general, there are two primary ways to CBS preparation: top-down and bottom-up, which are primarily dependent on the presence of apt stabilizers or combination of them to overcome CBS aggregation [82].Other unique techniques include heat transfer, remote loading, and spray drying [83].Cubosomes containing AT101 were prepared with help of GMO and pluronic F127 via top-down strategy to provide continuous AT101 release in the glioblastoma (GBM) treatment [84].Granisetronloaded CBS were made using a melt dispersion and emulsification approach to enhance GS transport to the brain via the IN route [64].Deruyver et al. produced paliperidone palmitate CBS nanoparticles using a bottom-up technique followed by spray drying [85].

CBS via intranasal drug delivery for ND therapy
Intranasal CBS delivery holds immense prospects for enhancing targeted delivery of actives to the CNS, especially in the treatment of major ND (Fig. 3).Some recent investigations which are described in following Table 1 yield valuable insights into its potential benefits in terms of bioavailability, permeability, prolonged drug release, etc.

Modulation in cubosomes for INDDS
CBS can be modified by using a variety of approaches to improve its efficacy for brain targeting via IN (Fig. 4, Table 2).CBS surface can be functionalized with different ligands, polymers, or surfactants to increase stability as well as mucoadhesion with the nasal mucosa [95].Additionally, penetration enhancers in CBS formulations help to increase medication permeability across the nasal mucosa, overcome obstacles, and improve bioavailability.Mucoadhesive agents aid to adhere to the nasal mucosa, extending residence time and increasing medication absorption [96].This is very useful for prolonged medication release.Loading CBS with therapeutic compounds, such as medicines, peptides, or nucleic acids, to provide a combination therapy approach for a variety of diseases, particularly neurological disorders.Cubosomes can be changed in response to environmental cues such as pH or temperature changes to facilitate passive distribution.Responsive CBS can release medications in a regulated manner in response to certain situations in the nasal cavity [86].Surface architecture and coating can have an impact on CBS-NP absorption mechanisms.
In situ IN gel undergoes sol-gel transformation when introduced into the nasal cavity (32-34 °C), thereby

Intranasal CBS thermogelling dispersion
In vivo (Albino rabbits) The relative bioavailability of cubosomal dispersion was approximately 12-fold larger than that of the oral aqueous suspension and 2.5fold more than that of the intranasal aqueous suspension of saquinavir mesylate [94] elevating the formulation's nasal residence time and penetration rate, leading to improved nasal absorption.
In situ IN gel undergoes sol-gel transformation when introduced into the nasal cavity (32-34 °C), thereby elevating the formulation's nasal residence time and penetration rate, leading to improved nasal absorption.[97].Pluronic F127 as well as pluronic F68 are widely used thermoresponsive pluronics in CBS preparation [80].Monoolein-water CBS like binary vesicles are known to self-assemble into thermodynamically stable, cubic crystalline structures [14].

Challenges in cubosomal approaches for INDD
NTB delivery offers noninvasive and patient-compatible administration route with fast drug action, precision drug targeting, and minimal adverse effects [100].Yet, the clinical translation of IN nanoformulations seems to be challenging owing to the problems associated with mucociliary clearance, enzymatic drug degradation, scalability, low NP translocation efficiency, mucosal toxicity as well as neurotoxicity [101].Another key hurdle for CBS in NTB drug delivery is establishing the spatial distribution of actives in brain tissue.Most of the reported studies have employed rodents as in vivo models.Although the anatomical nasal structures of rodents and humans share significant similarities, several characteristics must be examined for optimal compatibility.For instance, the respiratory region spans up to 90% of the human nose, while it is just 50% of the rodent nasal cavity [51].When an excess active moiety is administered across the nasal passage, the nasal cavity saturates [102], which may accelerate drug transport into the systemic circulation and cause side effects.It is difficult to administer a formulation directly to the nasal cavity.As a result, the amount of medicine that can be delivered nasally is limited.Apart from that, large-scale manufacturing of CBS can be challenging due to its high viscosity.Furthermore, as the CBS contains a large amount of water, there is less entrapment of water-soluble components.Leakage during storage, phase separation, and the likelihood of particle growth are all potential challenges to CBS formulations.The cytotoxicity of CBS is determined by internal morphology, excipient chemistry as well as the nature of stabilizers utilized.A study found that the CBS produced using poly(phosphoester) (PPE), a structural equivalent of the conventional F127, were considerably less hazardous than CBS containing F127 [103].Direct drug distribution via NTB route may lead to catastrophic, systemic consequences.Fast, yet excess drug delivery to the brain may activate the CNS immune system, resulting in drug toxicity.To minimize side effects and maximize therapeutic outcomes, clinical and pharmacometric data for each formulation needs to be carried out concurrently.This could ease the scale-up process for CBS.
Multiple factors of CBS manufacturing must be examined before their development and commercialization.Ease of scaling, long-term stability, and formulation safety are all important characteristics to consider.The utilization of microneedle-based devices is an attractive

Discussion
Intranasal administration is a noninvasive and userfriendly way that improves patient convenience and compliance when compared to other traditional drug delivery techniques.When it comes to nasal drug delivery, IN-CBS outperforms other vesicular drug delivery methods such as liposomes and niosomes.CBS has a bicontinuous cubic phase, resulting in a highly organized and stable structure [85,86].Since they are composed of amphiphilic lipids and surfactants, they have a distinct lattice structure that includes both hydrophilic and lipophilic areas.They offer greater protection for encapsulated pharmaceuticals due to their stable cubic phase structure, which reduces degradation and increases shelf life [90].Liposomes and niosomes are less stable, allowing for drug leakage and degradation.CBS's unique structural morphology allows for controlled and sustained release, resulting in long-term therapeutic effects.CBS produced from biocompatible lipids and surfactants have a low risk of toxicity and irritation, making them appropriate for intranasal administration.They offer the potential for tailored delivery to the brain via the olfactory and trigeminal nerve pathways.CBS are distinguished by their increased structural stability, higher drug absorption, bioavailability, controlled and sustained release, good biocompatibility, and unique targeting capability [105,106].These features make IN-CBS a better choice for some drug delivery applications than other vesicular systems.

Conclusion and future prospects
Designing vesicular systems for the treatment of brain diseases are particularly challenging due to the diverse physiological, metabolic, and biochemical barriers that form the BBB.These barriers aid to prevent medication particles from reaching the brain.The current outlook for patients with various types of CNS disorders remains bleak, yet recent improvements like CBS in drug delivery systems provide realistic hope that these significant obstacles can be overcome by noninvasive means.Intranasal administration has gained popularity in recent decades, surpassing oral or other methods.This article appraises on the structure of both the BBB as well as nasal anatomy, offering insights into the mechanisms governing nasal drug transport for CBS.Additionally, the nature of both the BBB and nasal anatomy is related to the mechanistic understanding of strategies driving nasal medication transport via CBS.Cubosomes (CBS) are cubic, liquid, crystalline phases with special features that help carry drug molecules to the brain.However, considerable advances will need mechanistic understanding prior to the translation of cubosome-based drug delivery systems.This comprehensive review outlines the distinct features and benefits of cubosomal drug delivery approach for intranasal delivery in the therapy of neurological illnesses.
The successful delivery of drugs from the nasal cavity to the brain still faces several challenges that need to be addressed.More detailed research is important to overcome these limitations and understanding the pathways involved is expected to be more promising.It is important to understand how drugs are delivered from the nasal cavity to the brain so that formulations can effectively reach targeted areas.Formulations need to be designed with apt physical strength to prevent the impact of extrinsic factors and maintain adherence at key points in the nasal cavity [64].Delivering large molecular weight pharmaceuticals, such as peptides and proteins to the brain, has posed a significant challenge.The development of CBS formulation technology will drive ongoing efforts to create new avenues for delivering drugs via nose-tobrain route.
Based on earlier studies, a considerable amount of research on delivering drugs from the nasal cavity to the brain is still in the preclinical stage, particularly in rodents [56,59,102,107].Yet, the number of preclinical studies far exceeds the limited cases that have progressed to the clinical stage.There is a need for pharmaceutical industries for investing on commercialization of CBS-based products.In order to address this challenge, it is crucial to comprehensively assess preclinical data, focusing specifically on effectiveness, safety, pharmacokinetics, targeting effectiveness, stability and adverse effects using suitable animal models [12].Additionally, it is important to verify the reproducibility of the findings by utilizing various animal models which would substantiate and enhance the reliability of neurological treatments.

Fig. 2
Fig. 2 Schematic diagram of the physiological systems involved in drug delivery from the nasal cavity to the brain

Table 1
Cubosomal platform for intranasal delivery of neurotherapeutics

Table 2
Surface engineering strategies of CBS-INDDS in treating ND