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International Journal of Pharmaceutical InvestigationNOW IN
Review

A Detailed Review on Bridging Niosomal Carriers for Nose to Brain Drug Delivery: Principles, Translational Pathways and Attributes

1★, 1, 1, 2★ Corresponding author

  1. 1Department of Pharmaceutics, CMR College of Pharmacy, Medchal, Kandlakoya, Hyderabad, Telangana, INDIA.
  2. 2Department of Pharmacognosy, CMR College of Pharmacy, Medchal, Kandlakoya, Hyderabad, Telangana, INDIA.

CORRESPONDENCE

Madhavi Nimmathota

Department of Pharmaceutics, CMR College of Pharmacy, Medchal, Kandlakoya, Hyderabad-501401, Telangana, INDIA.

madhavi@cmrcp.ac.in

Received: 15-04-2026; Revised: 24-06-2026; Accepted: 04-08-2026.

Volume 17, Issue 1 · pp. 51–62 · 2026 · DOI: 10.5530/ijpi.20270001

View on IJPI original site ↗

ABSTRACT

Non-invasive nasal drug delivery systems have emerged as a promising route for drug administration. It facilitates rapid therapeutic effect, bypass first pass metabolism, increase patient compliance and provides nose-to-brain drug delivery. The nasal mucosa possesses high vascularization and large surface area enabling efficient uptake of both systemic and locally administered drugs. Nasal administration is especially beneficial in emergency situations such as migraines, seizures, and severe pain. Nasal dosage forms have been developed to enhance drug retention and improve therapeutic efficacy. Niosomal carriers offer a versatile and clinically promising platform to overcome the anatomical and physiological barriers of nose-to-brain drug delivery, combining enhanced mucosal adhesion, tunable release kinetics, and improved drug stability to facilitate direct transport along olfactory and trigeminal pathways. This review synthesizes fundamental principles of niosome design, surfactant selection, bilayer composition, size and surface charge modulation, and functionalization strategies to illustrate how physicochemical attributes govern mucociliary clearance, epithelial uptake, and neuronal translocation. Critical attributes such as encapsulation efficiency, payload versatility, stability under nasal conditions, and potential for targeted ligand decoration are evaluated alongside strategies to mitigate immunogenicity and off target deposition. The niosomal systems poised to expand therapeutic options for central nervous system disorders via minimally invasive intranasal administration.

KEYWORDS

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FULL TEXT

INTRODUCTION

Several routes of drug administration exist to deliver the active molecule and achieve a therapeutic response. The primary routes of drug delivery include oral, intravenous, intramuscular, transdermal and intranasal administration. Oral drug delivery is the most widely used and convenient method but it often restricted due to first pass metabolism, gastric irritation and degradation of drugs through various enzymes. The gastro intestinal epithelium restricts drug permeability and absorption into the bloodstream through its mucus layer, metabolic enzymes, and tight junctions. Furthermore, fluctuations in pH and the composition of gut micro flora also affect drug stability and release, thereby decreasing overall bioavailability (Lou et al., 2023; Azman et al., 2022). The transdermal route is mainly restricted by the strong barrier function of the stratum corneum, which limits the penetration of large molecules, permitting only substances with a molecular weight below 500 Da to pass through effectively (Das et al., 2017). The intravenous administration poses risks including needle stick injuries, infections, phlebitis, thrombosis, and circulatory overload, making it invasive and less suitable for long-term use (Homayun et al., 2019). Further, the intravenous route requires skilled healthcare professionals, adherence to strict aseptic techniques, and patient cooperation, thereby increasing costs and limiting its applicability for large groups or multiple dosing schedules (Panza et al., 2022). The intramuscular injections are commonly used for vaccine delivery, they have several drawbacks, particularly for biopharmaceuticals like peptides and proteins. It often leads to low bioavailability and decreased immunogenicity, as proteins may form aggregates at the injection site, thereby compromising stability and effectiveness (Liang et al., 2016; Nanaki et al., 2017; Fletcher et al., 2018). To avoid all the drawbacks of various routes and to provide localized action, the current review focused to make a note of intranasal route. It administers drugs into the nasal cavity where absorption occurs across the respiratory and olfactory epithelia. The nasal mucosa is highly vascularized and linked to the brain through nerve pathways, forming direct connections for molecules to reach central nervous system targets without full systemic circulation and hepatic first pass loss. This anatomical advantage has driven renewed interest in intranasal strategies for neurotherapeutics, vaccines, and rapid symptomatic treatments (Ghosh et al., 2024).

Niosomes are considered advantageous over traditional drug formulations because they overcome several limitations associated with conventional dosage forms, including low bioavailability, rapid breakdown, and non-targeted drug distribution. Traditional formulations often result in fluctuations in drug levels and necessitate either higher or more frequent dosing, thereby elevating the risk of adverse effects. Composed of non-ionic surfactant bilayers, niosomes encapsulate both hydrophilic and lipophilic drugs, safeguarding them from degradation due to chemicals, enzymes, and metabolism. This encapsulation boosts drug stability and extends circulation time. Their ability to provide controlled and sustained drug release maintains therapeutic drug levels for prolonged periods, thereby reducing dosing frequency and improving patient adherence. The current review focus on the detailed description of nasal route applications in localized delivery through nanocarriers.

Search Strategy

A comprehensive literature search was conducted using databases including PubMed, Science Direct, and Google Scholar to identify relevant studies published between 2013 and 2025. Keywords employed in the search included "Niosomes," "Nose-to-brain delivery," "Intranasal drug delivery," "Blood-brain barrier," and "Nanocarriers." The search prioritized articles focusing on formulation attributes, preparation techniques like thin-film hydration and microfluidics, and in vivo efficacy in central nervous system disorders. References were screened to ensure they addressed the transport mechanisms via olfactory and trigeminal pathways.

Nasal drug delivery system

Nasal delivery system has been a well-established practice for several decades, and is a frequently employed method of administration for locally acting treatments for conditions such as allergic rhinitis, sinusitis, and congestion, and it is increasingly being utilized and investigated for systemic delivery, e.g., migraine, Alzheimer's and Parkinson's etc. (Williams et al., 2022). Nasal drug delivery systems enhance drug availability at the site of action by modifying its dissolution properties and permeation profile increasing its retention at the nasal mucosa. The nasal cavity's anatomy and physiology are the most important variables influencing nasal administration, primarily because of mucociliary clearance, and the complex shape of the nasal cavity, which influence the drug delivery (Hafne, 2022). The nasal cavity is a complex anatomical structure that forms a connection between nostrils and nasopharynx, performing several key functions such as respiration, smelling, and filtering airborne particles. The structure and composition of a nasal drug delivery system are vital to its effectiveness (Pal et al., 2024). The nasal anatomy is described in Figure 1.

Figure 1: Nasol anatomy highlighting drug absorbtion sites.

The nasal cavity is comprised of two distinct regions extending from the nostrils to the nasopharynx. The nasal cavity can be divided into three distinct areas: the vestibular area, the respiratory area, and the olfactory area. The area of the vestibular region is situated at the entrance of the nostrils, covers approximately 0.6 cm2, this region comprises nasal hairs, and few ciliated cells (Crisler et al., 2020). The nasal cavity is predominantly made up of the respiratory area, which accounts for up to 80-90% of its total volume. This section of the respiratory system is distinguished by a pseudostratified columnar epithelium and is the most vascular area. The respiratory epithelium is mainly made up of four different cell types: goblet cells, ciliated, non-ciliated columnar and basal cells. The olfactory region covers 10 cm2 (Keller et al., 2022; Chamanza et al., 2015). The nasal cavity's extensive surface area, is largely due to the presence of turbinates and meatuses (Helwany et al., 2021). The rich blood supply to the nasal mucosal lining facilitates the targeted distribution of absorbed molecules. The nasal mucosa vascularized by two different vessels, resistance vessels, are muscular vessels with a small lumen; capacitance vessels are thin-walled and elastic (Ugwoke et al., 2001, De et al., 2022). Administering therapeutic compounds through the nose presents a practical option for delivering treatments both directly to the local area and throughout the body. The nasal mucosa offers a considerable surface area that facilitates rapid onset of effects, enables direct access to the CNS, bypasses hepatic metabolism, and provides non-invasive characteristics; collectively, these features can optimize patient convenience, comfort and adherence. Intranasal treatment does not necessitate sterile preparations, it is non-invasive, painless, and can also be easily and quickly administered by the patient (Bhandwalkar et al., 2020).

The drug absorption rate is influenced by physiological factors, including the rate of nasal secretion, mucociliary movement, and metabolism (Kumar et al., 2016). This route also has certain limitations. Absorption through the nose is not possible for all drugs, and it depends on properties such as molecular weight, solubility, pKa, and lipophilicity. Drugs exhibiting low solubility, large molecular weights, or polar configurations may experience impaired absorption due to expedited clearance, reduced permeability, or enzymatic breakdown in the nasal passage (Aultonet al., 2013). The nasal mucosa is highly sensitive to irritation, and factors such as pH, dosage form type, excipients, and drug concentration have a significant impact on the absorption process. Various physiological barriers such as mucociliary clearance, nasal enzymes, and nasal blood flow, along with conditions like rhinitis, infections, and allergies, can impede drug absorption. Trapped drugs can also be limited in their ability to reach the epithelium by mucus (Ghori et al., 2015).

Strategies for enhancing nasal drug administration

The following methods were employed to improve the drug's accessibility and permeation through the nasal mucosa (jassim et al., 2018). Various strategies of nose to brain delivery are shown in Figure 2.

Figure 2: Strategies for nose to brain delivery

Increasing the residence time

Sustaining the drug retention in the cavity enhances the availability of drugs. Polymers like methylcellulose, HPMC, and carbopol enhance viscosity and serve as mucoadhesive agents to prolong clearance. Biodegradable microspheres can extend their stay in the nasal area by swelling in the nasal fluids and thickening the formulation's consistency.

Improving Nasal Absorption

Permeation enhancers increase the absorption of drugs across the nasal epithelial layer by modifying membrane permeability. They act by opening tight junctions, reducing mucociliary clearance rates, inhibiting enzymes, or decreasing mucus viscosity. An ideal enhancer should be potent, non-poisonous, non-inflammatory, compatible with medications, and function through safe, well-established processes. Examples of absorption enhancers include surfactants, cyclodextrins, fatty acid slats, phospholipids, bile salts, chelating agents, enzymatic inhibitors, cosolvents, prodrugs.

Targeted drug delivery

Various advanced delivery systems are capable of delivering the drug across the nasal mucosa and facilitate direct access to brain. Liposomes, niosomes, microspheres, nanoparticles, and in situ gelling systems can achieve nasal absorption without irritating the nasal mucosa and have good safety profile. Novel dosage forms with neutral or have a slightly negative charge exhibit improved diffuse, whereas positively charged systems frequently bind strongly to mucins and are rapidly cleared. Surface modification, especially through PEGylation, decreases mucus adhesion and improves stability (De et al., 2022).

Improving solubility and stability

Absorption of drug with low solubility and stability can be increased through improving the formulation strategies. Solubility can be improved by adjusting the pH. Stability and solubility of the drug can be enhanced by complex formation using cyclodextrins. Permeation of the drug can be increased by using solvents and cosolvents. Development of prodrugs with muco-penetrative agents, improves the stability of the drug (Keller et al., 2022).

Few reports demonstrated enhanced nasal drug absorption and proved through various reports that niosomal formulations significantly improve nasal drug delivery compared to traditional methods. Intranasal niosomal delivery of nefopam hydrochloride to rats resulted in a 4.77-fold rise in relative bioavailability relative to the oral solution, with notably higher peak plasma concentrations and a longer elimination half-life, suggesting improved permeation and prolonged systemic exposure through the nasal pathway (Abou-Taleb et al., 2018). In vitro testing of carvedilol-loaded mucoadhesive niosomes found a maximum of 4.8 times more drug release after 24 hr than the free drug, as well as roughly 1.7 times increase in release compared with uncoated formulations, highlighting improved drug availability at the site of absorption (Azrak et al., 2024). Additional studies indicate that surface-modified niosomes, such as chitosan-coated vesicles, exhibit stronger mucoadhesion and longer nasal residence time than unmodified nanoparticles. These properties enhance nasal epithelial permeation and nose-to-brain transport, demonstrating superior absorption and targeting efficiency of niosomal systems compared with other nanocarriers (Rinaldi, et al., 2018).

Nose-to-brain drug delivery

Blood brain barrier prevents entry of any pharmaceutical compounds into brain. A non-invasive approach has been designed to deliver drugs directly to the brain by avoiding the blood-brain barrier via intranasal administration through the olfactory nerve pathway (Huanget al., 2023). The nasal cavity's olfactory epithelium serves as a link between the external environment and central nervous system (Shen et al., 2025). This distinctive anatomy of the olfactory epithelium allows the intranasal delivery approach to transport therapeutics across the olfactory epithelium to the olfactory bulb in the brain (Norwood et al., 2019; Spera et al., 2023). The pathways of nose to drug are shown in 3.

Targeted drug delivery from the nasal cavity into the brain takes place along multiple routes, which involve both direct neural pathways via the olfactory and trigeminal nerves and indirect systemic transport through the blood vessels and lymphatic system (Mittal et al., 2014). Delivering drugs to the brain through the direct olfactory and trigeminal nerve pathways offers a rapid and efficient method (Keller et al., 2022). The olfactory pathway involves intra- and extra-neuronal transport as well as paracellular and transcellular mechanisms, enabling drugs to cross the olfactory epithelium and reach the olfactory bulb via the cribriform plate (Bourganis et al., 2018).The intracellular pathway includes axonal transport, endocytosis by sensory cells and exocytosis into the olfactory bulb (Crowe et al., 2018).The extracellular pathway directly delivers the drug through the paracellular space, and perineural space into the subarachnoid space around the brain (Selvaraj et al., 2018).

The trigeminal nerve offers an alternative pathway to both the rostral and caudal brain regions via its ophthalmic and maxillary branches (Lochhead et al., 2020). Transport of substances through the respiratory epithelium to the brain may occur indirectly, but the ability of molecules to pass through the BBB is still the main limiting factor and tends to favor small, lipid-loving molecules (Crowe et al., 2018). The blood–brain barrier restricts the effective distribution of many CNS treatments; nonetheless, the intranasal route facilitates direct drug delivery to the brain by circumventing the BBB. Intranasal delivery offers a more effective route for transporting drugs than intravenous delivery (Gharbavi et al., 2023).

Nose-To-Brain Mechanisms

Following intranasal administration, formulations of drugs within the nasal cavity's olfactory and upper respiratory areas interact with the nasal mucosa and cross the epithelial barrier through transport between tight junctions, diffusion across epithelial cells, or endocytosis, especially in the case of peptides, proteins, and nanoparticulate systems. After penetrating the epithelial layer, drugs reach the nerve pathways of the olfactory and trigeminal systems, where they are primarily transported along nerve sheaths to the olfactory bulb and other brain regions within minutes via extracellular or perineural transport, with lesser contributions from intracellular axonal transport (Lochhead and Thorne, 2012). Simultaneously, transport via the trigeminal nerve enables drug distribution to deeper brain structures including the brainstem and cerebellum (Pardeshi et al., 2013). Following this, drug molecules reach the brain's interstitial and cerebrospinal fluids, resulting in a broad distribution throughout the central nervous system with limited systemic exposure and fewer peripheral side effects.

Factors Affecting Nose To Brain Delivery

The process of nasal absorption for delivering drugs directly to the brain is affected by the attributes of the drug, the characteristics of its formulation, and the conditions within the nasal cavity. Drugs with molecular weights under 1000 Da (Pires et al., 2022) and higher lipophilicity tend to pass through the nasal epithelium more easily, although solubility, stability, and pH in comparison to the drug's pKa also impact absorption (Madden et al., 2023). Factors in formulation like particle size, viscosity, osmolarity, and the use of permeation enhancers or mucoadhesive agents influence residence time and mucosal penetration (Shen et al., 2025; Katare et al., 2024). The nasal mucosal integrity, blood flow, temperature, humidity, mucociliary clearance, and mucus production all influence the way drugs are absorbed, which underscores the importance of developing formulations that are tailored to achieve effective delivery of drugs directly to the brain (Cingi et al., 2021; Nguyen et al., 2025; Lee et al., 2021).

Niosomes For Brain Targeting

Intranasal brain targeting may be made more effective through the use of advanced drug delivery systems, which can help to overcome the issue of poor drug bioavailability (Fahmy et al., 2020). Multiple studies have shown that various nanocarriers, such as liposomes, dendrimers, microspheres, nano-emulsions, and carbon-based Nano-formulations, can successfully deliver drugs to the brain via the nose (Crowe, 2018). The ability of niosomes to safeguard drugs in biological fluids and deliver them effectively to targeted cells makes them promising and versatile nasal carriers (Nguyen et al., 2025).

The simplicity and affordability of their manufacturing process, combined with its scalability, help address the challenges linked to liposomes, including high production costs and instability issues. As a result of these advantages, niosomes have garnered significant interest in pharmaceutical uses such as anticancer, antifungal, vaccine, and gene delivery (Thabet et al., 2022; Moammeri et al., 2023). Niosomes provide various benefits for nasal drug delivery, including increased drug stability, better permeation across the nasal mucosa, and protection of encapsulated drugs from enzymatic breakdown. Their mucoadhesive properties allow for increased residence time, thereby overcoming rapid mucociliary clearance to improve absorption and bioavailability.

Niosomes allow for controlled and prolonged release of medications, accommodate both hydrophobic and hydrophilic drugs, and can facilitate direct delivery to the brain via the nose by circumventing the blood-brain barrier. Systemic side effects are reduced, enabling localized delivery and requiring lower doses. In order to overcome the challenges of nasal drug delivery, such as low dosage, degradation, rapid clearance and poor permeability of specific drugs, specialized formulation techniques are necessary.

Attributes Of Niosomes Facilitating Nose-To- Brain Dug Delivery

Niosomes are particularly suitable for Nose-to-Brain (N2B) delivery because of their nanoscale, enabling them to traverse the mucus layer and access the olfactory and respiratory epithelium. Small vesicles (100-250 nm) in size exhibit prolonged residence within the nasal mucosa, which in turn enhances their absorption and transport along the olfactory and trigeminal pathways. The noisome bilayer composition improves drug stability and allows for controlled release, with surfactants functioning as permeation enhancers by temporarily opening tight junctions to facilitate both paracellular and transcellular transport. Positively charged niosomes interact well with the nasal mucosa which is negatively charged, enhancing mucoadhesion and boosting drug bioavailability in the brain. Chitosan-coated nanocarriers below 300 nm have demonstrated efficient transcellular transport to the brain (Nerli et al., 2023).

The hydration of niosomal vesicles facilitates drug penetration by temporarily fluidizing the mucus layer and increasing diffusion. Surfactants like Span, Tween, and Cremophor also function as chemical penetration enhancers, which interact with mucosal lipids and proteins to boost drug permeation through the nasal epithelium without causing damage. Research has shown that intranasal niosomal systems greatly increase brain bioavailability, resulting in a 2-7-fold higher brain delivery compared to conventional intranasal solutions or gels. Strategies like ensuring pH compatibility, incorporating mucoadhesive agents to extend residence time, and using absorption enhancers or advanced nanocarrier systems are crucial to enhance drug stability, permeability, and overall therapeutic effectiveness (Nguyen et al., 2025).

Broad comparative reviews also highlight that niosomal nanocarriers combine the advantages of both liposomes and polymeric nanoparticles such as the ability to encapsulate hydrophilic and lipophilic drugs with extended stability while being more cost-effective and less complex to manufacture reinforcing their practical superiority over certain lipid-based and polymeric systems in nano-drug delivery applications (Witika et al., 2022). Studies of physiochemical properties show that niosomes retain stability and permeability similar to liposomes, but have enhanced protection against oxidation and hydrolysis due to their non-ionic surfactant structure (Bartelds et al., 2018). Dendrimers offer high drug-loading capacity, but their intricate synthesis and potential for harming cells hinder their use, in contrast to niosomes, which show enhanced compatibility with living tissues and simplified preparation methods (Kazi et al., 2010). Niosomes enable efficient encapsulation of both hydrophilic and lipophilic drugs while avoiding the use of harsh organic solvents commonly required in polymeric nanoparticle preparation. Niosomes maintain their structural integrity and prolong drug release, in contrast to solid lipid nanoparticles which are limited by restricted drug loading and storage instability (Pardeike et al., 2009). Overall, niosomes offer a well-balanced combination of stability, safety, versatility, and cost-effectiveness among available nanocarrier systems.

COMPONENTS OF NIOSOMES

Non-ionic surfactants

Non-ionic surfactants are crucial for the formation of niosomes due to their amphiphilic nature which includes a polar head group and a non-polar hydrophobic tail. In comparison to anionic, cationic, and amphoteric surfactants, these surfactants exhibit greater stability and lower toxicity. They also function as wetting agents and emulsifiers, increasing solubility, permeability, and the absorption of drugs, while reducing the risk of hemolysis and irritation (Moghtaderi et al., 2022). The surfactants commonly used in niosomes include sorbitan esters, polysorbates and Brij 35. Three key factors, the hydrophilic-lipophilic balance, gel–liquid transition temperature and critical packing parameter, significantly impact entrapment efficiency (Sharma et al., 2015). Surfactants with low HLB values, such as Span 60, are reported to result in the maximization of EE, especially for lipophilic drugs (Wu et al., 2021; Bnyan et al., 2018).

Cholesterol

Cholesterol serves as a widespread component of niosomes, contributing to the stability of the vesicles and the encapsulation of the drug. It is structurally a cyclopentanoperhydrophenanthrene sterane, composed of four fused rings (Bautista-Solano et al., 2025). The cholesterol enhances membrane cohesion and mechanical strength in niosomes, reduces their bilayer flexibility, controls drug permeability, increases the phase transition temperature, and minimizes drug leakage, thereby increasing encapsulation efficiency and stability. The ratio of surfactant to cholesterol has a significant impact on the structure and viscosity of vesicles. Increasing the cholesterol concentration has been proven to enhance the encapsulation efficiency of hydrophilic markers like carboxy fluorescein in a linear manner, by enhancing the packing of the bilayer and impeding transport across the membrane (Bhardwaj et al., 2020; Chen et al., 2019).

Charge-inducing molecules

Charge-inducing molecules are incorporated into niosomal formulations to give them a positive or negative surface charge, which stabilizes the vesicles through electrostatic repulsion and stops them from aggregation (Lu et al., 2020). The zeta potential reflects its effect, with values >+30 mV or <-30 mV represent greater stability, while values between 5-15 mV are in the flocculation region (Umbarkar, 2020). Anionic charge inducers typically used are dicetyl phosphate and phosphatidic acid, while cationic agents comprise stearyl amine, sodium stearoyl lactate, and stearyl pyridine chloride (Mohanty et al., 2018). Charge inducers can also enhance encapsulation efficiency and influence vesicle size.

Hydration medium

In niosome preparation, the hydration medium is a crucial element and is usually a buffer chosen based on the solubility and stability of the drug. Buffer pH has a significant impact on vesicle formation, drug loading, and stability (Unal et al., 2023). Selecting a suitable hydration medium, taking into account the physicochemical properties of the drug, is crucial for forming stable niosomes that can efficiently transport drugs (Figure 3).

Figure 3: Pathways of Nose to Brain Delivery.

PREPARATION METHODS

Some of the commonly employed preparation methods for niosomal formulation are mentioned in Figure 4.

Figure 4: Niosomes preparation Methods.

Thin film hydration method

The Thin-Film Hydration (TFH) technique, is the most commonly used approach for niosomes preparation (Gharbavi et al., 2023). In this method, cholesterol, non-ionic surfactant, and charge-inducing agents are dissolved in a volatile organic solvent, such as diethyl ether, ethanol or chloroform, inside a round-bottom flask. A thin dry lipid layer is produced on the flask wall by evaporating the solvent using a rotary evaporator. The film is then hydrated with a water-based phase while being gently mixed, leading to the formation of multilamellar niosomes. Drugs that are hydrophilic are incorporated in the aqueous phase, whereas drugs that are hydrophobic are incorporated in the organic phase prior to film formation. The subsequent step involves hydrating the film by gently mixing it with an adequate aqueous phase, resulting in the swelling and spontaneous self-assembly of surfactant molecules into multilamellar niosomal vesicles.

Reverse phase evaporation

This method is frequently employed to manufacture large unilamellar vesicles. This method involves blending cholesterol and surfactant in various molar ratios in an organic solvent mixture (Alle et al., 2021). A rotary evaporator is employed to evaporate the solvent, resulting in the formation of a thin dry lipid film. The film is subsequently dissolved in appropriate volume of ether, followed by the addition of a specified amount of the drug dissolved in an organic solvent such as acetone combined with buffer (pH 7.4). The mixture is subjected to a bath sonicator for a few minutes, manually agitated, and re-sonicated to achieve uniform dispersion.

Ethanol injection method

An ethanolic lipid solution is readily introduced into an aqueous phase, resulting in the formation of small unilamellar vesicles. Co-solvents such as isopropanol can be added to increase solubility and increase drug entrapment (Machado et al., 2020; Estupinan et al., 2020). The injection temperature and speed can be adjusted to control size and aggregation of vesicles, thus offering flexibility in formulation. This technique is straightforward, cost-effective, and can be easily scaled up without the need for advanced machinery. Niosomes produced using this method is typically smaller than those produced by thin-film hydration and microfluidics.

Microfluidic method

Niosomes are fabricated using microfluidic equipment consisting of central and side passageways, through which the organic and aqueous liquids are propelled at predetermined flow rates into a reaction compartment (Bhardwaj et al., 2020). The rapid mixing process within the microchannels results in the spontaneous formation of small, uniform niosomes, which are then collected from the outlet channel (Machado et al., 2020). This approach enables precise control over particle size and polydispersity by modifying the flow rate ratio and processing conditions. Benefits of this technique comprise minimal solvent use, replicability, expandability, and the capability to manufacture cholesterol-free formulations (Garcia-Manrique et al., 2019; Mawazi et al., 2025). Niosomes produced by microfluidics are typically smaller than those created through thin-film hydration.

Ether injection method

This technique for niosomal preparation dissolving non-ionic surfactants and cholesterol in ether, often combined with a small amount of co-solvent. The resulting solution is then injected into a buffered solution, under constant stirring and controlled temperature. The temperature difference between the organic and aqueous phases promotes spontaneous formation of niosomal vesicles. This method allows for the gradual and controlled formation of vesicles, with size and characteristics influenced by injection rate, temperature, and stirring conditions (Amreen et al., 2023).

The Bubble Technique

This method eliminates the need for organic solvents and necessitates the use of a three-neck glass flask placed in a water bath to maintain the temperature. The first neck accommodates a thermometer, the second is employed for the inlet of nitrogen gas, and the third is connected to a water-cooled reflux condenser. Mixture of surfactant, cholesterol, and buffer is then heated sequentially to 70ºC to produce a dispersion. Next, the mixture undergoes high-shear homogenization for 15 sec before being subjected to nitrogen bubbling at a temperature of 70ºC immediately afterwards. This process yields large unilamellar vesicles (Bhardwaj et al., 2020). Many niosomal formulations are developed in recent years for nose-to-brain drug delivery to treat various CNS related disorders. Few developed niosomal nasal formulations are mentioned in Table 1.

Table 1: Niosomal formulations developed for nose-to-brain delivery.
Sl. No.DrugDosage formTreatmentOutcomeReferences
1.Ondansetron HClNiosomal gelPrevent nausea and vomiting caused by chemo
therapy		The formulation exhibited a high drug entrapment efficiency of 76.13±1.2% and achieved sustained drug release rates of 91.76% from the niosomes and 70.6% from the in situ gel over a period of 12 hr, suggesting efficient drug loading and controlled release properties.(Teaima et al., 2020)
2.LacosamideChitosan-coated niosomes (niosomal dispersion)EpilepsyThe vesicle size is approximately 194 nm, it has an entrapment efficiency of 58.3%, a positive zeta potential of +35.6 mv, and achieves sustained drug release of 81.3% after 8 hr, also enhancing nasal diffusion.(Tulbahet al., 2023)
3.Bromocriptine
mesylate		NiosomesParkinson’s DiseaseSignificant increases in brain bioavailability (approximately 10.4-fold) were observed, along with high direct transport (91.06%), an enhanced pharmacodynamic response achievable with a 10-fold reduction in dose, and no notable toxicity.(Sita et al., 2020)
4.MethotrexateNiosomal thermo-sensitive in situ nasal gelBrain tumors and CNS malignanciesThe in situ gel provided prolonged nasal residence, facilitated controlled release, enhanced brain concentration, decreased systemic exposure, and minimized side effects in comparison to MTX solution.(Ourani et al., 2022)
5.Folic acidNiosomesAlzheimer’sOptimized niosomes (Span 60: Cholesterol in a 1:1 ratio) demonstrated good stability at 4ºC and 25ºC, and they facilitated increased nasal absorption approximately 48% within 6 hr, which suggests enhanced bioavailability relative to conventional formulations.(Ravouru et al., 2013)
6.Buspirone HydrochlorideNiosomal in situ nasal gelTreatment of anxiety disordersThe sustained release of drugs (~83.5% ex vivo in 8 hr) along with stable vesicles and enhanced nasal absorption indicates the potential for effective intranasal delivery compared to conventional gels.(Mathure et al., 2018)
7.ClonazepamChitosan-coated niosomesanxiety, seizuresThe formulation remained stable for 12 weeks, displayed a sustained release pattern of approximately 50% in 4 hr, enhanced mucoadhesion, experienced a 10-fold increase in nasal permeability, and exhibited a 1.5-fold decrease in toxicity relative to the free drug.(Sharma et al., 2015)
8.CiticolineNiosomal in situ nasal gelManagement of epilepsyThe enhanced nasal permeation led to the prolonged nasal residence of the incorporated in situ gel, improved brain uptake and demonstrated significant protective effects against seizures at a low dose, compared to the oral drug solution.(Bekhet et al., 2022)
9.Kynurenic AcidNiosomal in situ nasal gelNeuroinflammationThe niosomal gel formed a stable structure with effective drug encapsulation, and intranasal delivery greatly increased bioavailability compared to oral administration.(Chettupalli et al., 2025)
10.RisperidoneNiosomal dispersionManagement of schizophreniaThe nanoparticles exhibited good stability and prolonged release properties, resulting in increased nasal absorption and enhanced delivery of the drug to the brain, demonstrated by a 2.32-fold higher nasal permeation rate compared to the suspension.(Qureshi et al., 2019)
11.OlanzapineNiosomal dispersionManagement of schizophreniaHigher nasal absorption and prolonged delivery compared to solution formulation; stable over storage; optimised formulation demonstrated a 3-fold increase in brain concentration, indicating enhanced bioavailability.(Khallaf et al., 2020)
12.PentamidineGlutamate-coated niosomal dispersionPotential treatment of CNS infectionsCoated niosomes exhibited stability with mucoadhesive characteristics; the entrapment and retention within the nasal cavity indicate a possibility for effective nose-to-brain delivery and enhanced bioavailability.(Rinaldi et al., 2018)
13.AmisulprideNiosomal in situ nasal gelManagement of schizophreniaThe nasal gel ensured stable encapsulation of the drug, controlled its release, and facilitated enhanced delivery of the drug to the brain, thereby improving bioavailability.(Patil et al., 2023)
14.FlibanserinNiosomal in situ nasal gelTreatment of hypoactive sexual desire disorderThe intranasal niosomal in situ gel exhibited stability and a well-structured form, displayed efficient drug encapsulation, promoted enhanced nasal permeation, and significantly increased brain and systemic availability, thereby demonstrating effective nose-to-brain delivery compared to conventional oral administration.(Moammeri et al., 2023)
15.Valproic AcidNiosomal thermo-sensitive in situ nasal gelTreatment of epilepsy and seizuresThe niosomal in situ nasal gel demonstrated effective drug encapsulation, controlled drug release, and acceptable mucoadhesive and gelation properties. The formulation proved safe to nasal tissue, increased drug accessibility, and showed potential for effective nose-to-brain delivery at reduced dosages and with enhanced patient convenience.(Chaudhariet al., 2013)

FUTURE DIRECTIONS

Nose-to-brain delivery using niosomal formulations appears promising, but several challenges need to be overcome for clinical application. Future studies on nose-to-brain delivery of niosomal formulations should concentrate on improving targeting efficiency, safety, and clinical applicability. Niosomes modified to interact with the surface may greatly enhance targeted transport through the olfactory and trigeminal pathways while reducing systemic exposure. Ensuring reproducibility and scalability for industrial production necessitates optimizing niosomal composition, vesicle size, and manufacturing processes. Additionally, thorough assessment of long-term safety, neurotoxicity, and immunogenicity post repeated intranasal administration is also essential. Future research should focus on the development of the standard regulatory guidelines for intranasal carriers.

CONCLUSION

The nasal route functions as an alternative method of administration for conventional and parenteral methods. It provides a rapid onset of action and bypass hepatic first-pass metabolism. This also enables brain delivery through the trigeminal and olfactory pathways. Various formulation approaches have been investigated to improve drug solubility, absorption, and residence time within the nasal cavity. Niosomal systems have evolved as an advanced delivery platform, offering improved drug stability, controlled release, and increased permeation through the nasal mucosa. Their capacity to enclose both hydrophilic and lipophilic drugs enhances bioavailability and makes it possible for targeted and site-specific delivery, including potential transport across biological barriers such as the nasal mucosa and the blood–brain barrier. Niosomes can prolong nasal residence time, improve drug stability and also facilitate direct drug delivery to brain through olfactory and trigeminal pathways improving the bioavailability and reducing the side effects.

ACKNOWLEDGEMENT

The authors acknowledge the Department of Pharmaceutics CMR College of Pharmacy, Hyderabad, for providing the necessary facilities and support to conduct this review.

ABBREVIATIONS

BBB
Blood-Brain Barrier
CNS
Central Nervous System
EE
Entrapment Efficiency
HLB
Hydrophilic-Lipophilic Balance
HPMC
Hydroxypropyl Methylcellulose
MTX
Methotrexate
N2B
Nose-to-Brain
TFH
Thin Film Hydration.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

AUTHORS CONTRIBUTIONS

All authors contributed equally.

REFERENCES

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Nimmathota, M., Sravani, B., Priya, M. H., & Vattikuti, U. M. R. (2026). A Detailed Review on Bridging Niosomal Carriers for Nose to Brain Drug Delivery: Principles, Translational Pathways and Attributes. International Journal of Pharmaceutical Investigation, 17(1), 51–62. https://doi.org/10.5530/ijpi.20270001