Intranasal Drug Delivery Systems for Brain Targeting: From Biological Barriers to Nanocarrier-Based Solutions

Central nervous system (CNS) disorders, including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, stroke, brain tumors, and psychiatric disorders, represent a major global health burden and are leading causes of disability and mortality worldwide. The treatment of these disorders remains highly challenging due to the complex structure and function of the brain, as well as the presence of protective physiological barriers. Among these, the blood–brain barrier (BBB) plays a crucial role in maintaining brain homeostasis by tightly regulating the entry of substances from systemic circulation into the brain. However, this selective permeability significantly limits the delivery of therapeutic agents, allowing only small, lipophilic molecules to pass while restricting most drugs, including macromolecules and hydrophilic compounds.^1,

As a result, more than 90% of potential CNS drugs fail during development due to their inability to effectively cross the BBB and reach therapeutic concentrations in the brain . Conventional drug delivery approaches such as oral and intravenous administration often lead to poor bioavailability, systemic side effects, and non-specific drug distribution, which further reduce therapeutic efficacy. In many cases, higher doses are required to achieve desired drug levels in the brain, increasing the risk of toxicity and adverse effects.

These limitations highlight the urgent need for targeted brain drug delivery strategies. Brain targeting aims to enhance drug concentration at the site of action while minimizing systemic exposure, thereby improving therapeutic outcomes and patient compliance. In recent years, innovative approaches such as nanocarrier-based systems and intranasal drug delivery have gained significant attention due to their ability to bypass the BBB and directly deliver drugs to the brain via neural pathways. These advanced strategies offer promising solutions to overcome existing barriers and improve the treatment of CNS disorders.²

This review focuses on the emerging potential of intranasal drug delivery systems as a non-invasive and efficient strategy for brain targeting in the management of central nervous system (CNS) disorders. It comprehensively covers the anatomical and physiological aspects of the nasal cavity and their relevance to drug transport pathways, particularly the olfactory and trigeminal nerve routes that enable direct nose-to-brain delivery. The review further discusses the major biological barriers, including the nasal mucosa, enzymatic degradation, mucociliary clearance, and the blood–brain barrier, which collectively limit effective drug delivery to the brain.

1. Anatomy and Physiology of the Nasal Cavity

The nasal cavity is the first segment of the respiratory tract, responsible for air conditioning (warming, humidification, filtration) and olfaction, and it plays a crucial role in nose-to-brain drug delivery pathways. The nasal cavity has an approximate volume of 15–20 mL and a surface area of about 150–160 cm², which is significantly increased by the presence of turbinates that create folds within the cavity.
This large surface area and rich vascularization make the nasal cavity an attractive site for systemic and brain-targeted drug delivery.³

2.1 Structure of the Nasal Cavity

The nasal cavity is anatomically divided into three distinct regions: the vestibular, respiratory, and olfactory regions, each with unique structural and functional characteristics.

2.1.1 Vestibular Region

The vestibular region is the anterior part of the nasal cavity located just inside the nostrils.
It is lined with stratified squamous epithelium similar to skin and contains coarse hairs known as vibrissae. These hairs act as a physical barrier that traps large particulate matter such as dust and microbes. Sebaceous and sweat glands present in this region further contribute to its protective function. Due to its thick epithelial lining and low permeability, the vestibular region plays a minimal role in drug absorption.^3,4

2.1.2 Respiratory Region

The respiratory region constitutes the largest portion of the nasal cavity and is primarily responsible for conditioning inhaled air. It is lined with pseudostratified ciliated columnar epithelium containing goblet cells that secrete mucus. The mucus layer traps inhaled particles, while the coordinated beating of cilia transports the mucus toward the nasopharynx in a process known as mucociliary clearance. The rate of mucociliary clearance is approximately 5–10 mm per minute, which can influence the residence time of drugs in the nasal cavity. This region is highly vascularized, facilitating rapid absorption of drugs into systemic circulation. Therefore, the respiratory region is considered the primary site for systemic drug delivery via the intranasal route.^4,5

2.1.3 Olfactory Region

The olfactory region is located at the roof of the nasal cavity, covering the superior turbinate and part of the nasal septum. It occupies a relatively small surface area of approximately 2–12.5 cm² but has significant functional importance. This region is lined with specialized olfactory epithelium composed of olfactory receptor neurons, supporting cells, and basal cells. The olfactory neurons extend their axons directly into the olfactory bulb of the brain, forming a direct connection between the nasal cavity and the central nervous system. This unique anatomical feature enables direct transport of drugs to the brain, bypassing the blood-brain barrier. As a result, the olfactory region is a key target for nose-to-brain drug delivery systems.^4,5

2.1.4 Blood Supply of the Nasal Cavity

The nasal cavity has an extensive blood supply derived from both the internal and external carotid arteries. Branches of the ophthalmic artery, including the anterior and posterior ethmoidal arteries, supply the superior portions of the nasal cavity. The sphenopalatine artery, a branch of the maxillary artery, is the major contributor to the posterior nasal cavity. Additional supply is provided by the greater palatine artery and the superior labial artery. These arteries form an anastomotic network known as Kiesselbach’s plexus in the anterior nasal septum, which is a common site for epistaxis. The rich vascularization enhances the absorption of drugs into systemic circulation and contributes to rapid onset of action. Venous drainage occurs through the facial vein, pterygoid plexus, and cavernous sinus, providing pathways for systemic distribution.^6,7

2.1.5 Innervation of the Nasal Cavity

The nasal cavity is innervated by both sensory and autonomic nerves, which regulate its physiological functions. The olfactory nerve (cranial nerve I) is responsible for the sense of smell and originates from olfactory receptor neurons in the olfactory epithelium. The trigeminal nerve (cranial nerve V) provides general sensory innervation, including sensations of pain, temperature, and touch. The ophthalmic division (V1) supplies the anterior part of the nasal cavity via the anterior ethmoidal nerve, while the maxillary division (V2) supplies the posterior region through branches such as the nasopalatine nerve. Autonomic innervation includes parasympathetic fibers from the facial nerve (cranial nerve VII), which stimulate mucus secretion, and sympathetic fibers that regulate vasoconstriction and blood flow. These neural components play an important role in nasal physiology and influence drug absorption and clearance.^8,9

2.1.6 Olfactory Nerve Pathway

The olfactory pathway is one of the primary routes for direct drug delivery from the nasal cavity to the brain. Drugs deposited in the olfactory region can be transported across the olfactory epithelium via intracellular and extracellular mechanisms. Intracellular transport involves endocytosis of drug molecules into olfactory neurons followed by axonal transport to the olfactory bulb. Extracellular transport occurs through perineural channels surrounding olfactory neurons. Once in the olfactory bulb, drugs can further distribute to other regions of the brain. This pathway bypasses the blood-brain barrier, making it highly advantageous for delivering therapeutic agents to the central nervous system.^9,10

2.1.7 Trigeminal Nerve Pathway

The trigeminal nerve pathway represents an additional route for nose-to-brain drug delivery.
Drugs absorbed in both the respiratory and olfactory regions can be transported along the trigeminal nerve branches. These branches project to the brainstem and spinal cord, allowing drugs to reach deeper brain structures. Compared to the olfactory pathway, the trigeminal pathway provides broader distribution within the central nervous system. This pathway is particularly important for drugs that do not efficiently utilize the olfactory route. Together, the olfactory and trigeminal pathways form complementary mechanisms for effective nose-to-brain drug delivery.¹¹

2. Biological Barriers to Brain Drug Delivery

Efficient delivery of drugs to the brain is significantly restricted by multiple physiological and anatomical barriers that maintain central nervous system (CNS) homeostasis. These barriers protect the brain from harmful substances but also limit the of therapeutic agents, especially large and hydrophilic molecules. The major barriers include the blood–brain barrier (BBB), blood–cerebrospinal fluid barrier (BCSFB), nasal epithelial barrier, mucociliary clearance, and enzymatic degradation within the nasal cavity. Understanding these barriers is essential for designing effective nose-to-brain drug delivery systems.¹²

3.1 Blood–Brain Barrier (BBB)

The blood–brain barrier is a highly selective and dynamic interface that separates the systemic circulation from the brain parenchyma. It is primarily composed of brain capillary endothelial cells connected by tight junctions, along with pericytes, astrocyte end-feet, and a basement membrane. These tight junctions restrict paracellular transport, allowing only small, lipophilic molecules (generally <400 Da) to diffuse passively across the barrier. Hydrophilic drugs and macromolecules require specialized transport systems such as carrier-mediated transport or receptor-mediated transcytosis. Efflux transporters such as P-glycoprotein actively pump many drugs back into the bloodstream, further limiting drug accumulation in the brain. This active efflux mechanism is one of the major reasons for the poor brain bioavailability of many therapeutic agents. Enzymatic activity within the endothelial cells can metabolize drugs before they reach the brain tissue. Due to these combined features, approximately 98% of small-molecule drugs and nearly all large molecules fail to cross the BBB effectively.¹³

3.2 Blood–Cerebrospinal Fluid Barrier (BCSFB)

The blood–cerebrospinal fluid barrier is another important interface that regulates the exchange of substances between the blood and cerebrospinal fluid (CSF). It is primarily located at the choroid plexus, where epithelial cells form tight junctions that restrict the passage of molecules. Unlike the BBB, the capillaries in the choroid plexus are fenestrated, but the epithelial layer provides the main barrier function. Transport across the BCSFB occurs through selective transporters and active secretion mechanisms. Although the BCSFB is less restrictive than the BBB, it still limits many drugs into the CSF. Drugs entering the CSF must further diffuse into brain tissue, which can be slow and inefficient. The BCSFB plays a crucial role in maintaining CSF composition and can act as a secondary barrier in brain drug delivery. Targeting this barrier is less common but may be beneficial for certain CNS disorders.¹⁴

3.3 Nasal Epithelial Barrier

The nasal epithelium acts as the first biological barrier encountered by intranasally administered drugs. It consists of tightly packed epithelial cells connected by tight junctions, which limit paracellular drug transport. The epithelial barrier varies across different regions of the nasal cavity. The respiratory epithelium is relatively permeable compared to the olfactory epithelium, which is specialized for neuronal signaling.¹⁵

Drug absorption across the nasal epithelium occurs through:

• Transcellular (lipophilic drugs)
• Paracellular (hydrophilic drugs, limited by tight junctions)
• Endocytosis/transcytosis (macromolecules and nanoparticles)

3.4 Mucociliary Clearance Mechanism

Mucociliary clearance is a critical mechanism of the nasal cavity that removes inhaled particles and pathogens. It involves the coordinated movement of cilia that transport mucus toward the nasopharynx.

The mucus layer consists of two phases:

• A gel layer that traps particles
• A sol layer that allows ciliary movement

The average mucociliary clearance time in humans is approximately 15–30 minutes.
This rapid clearance significantly reduces the residence time of drugs in the nasal cavity, thereby limiting drug absorption.¹⁶

3.5 Enzymatic Degradation in the Nasal Cavity

The nasal cavity contains various enzymes that can metabolize drugs before they are absorbed.
These include:

• Cytochrome P450 enzymes
• Peptidases
• Proteases

These enzymes are present in the nasal mucosa and mucus layer and can degrade peptides, proteins, and other labile drugs. As a result, the bioavailability of such drugs is significantly reduced following intranasal administration. All these barriers collectively limit efficient drug delivery to the brain.
While the BBB and BCSFB restrict systemic delivery, nasal barriers such as epithelial tight junctions, mucociliary clearance, and enzymatic degradation affect intranasal drug administration. The intranasal route offers a unique advantage by partially bypassing the BBB through olfactory and trigeminal pathways, but it still faces local nasal barriers.¹⁷

3. Mechanisms of Nose-to-Brain Transport

Nose-to-brain drug delivery is an emerging approach that enables direct transport of therapeutic agents from the nasal cavity to the central nervous system. This route bypasses the blood–brain barrier and allows rapid drug delivery to the brain. The transport of drugs from the nasal cavity to the brain occurs through multiple pathways, primarily involving the olfactory and trigeminal nerves, as well as intracellular and extracellular mechanisms. In addition, drugs may also reach the brain indirectly via systemic absorption followed by crossing the blood–brain barrier.^17,18

4.1 Olfactory Pathway

The olfactory pathway is the most direct and widely studied route for nose-to-brain drug delivery. It originates from the olfactory epithelium located in the upper region of the nasal cavity. Olfactory receptor neurons present in this region extend their axons through the cribriform plate to the olfactory bulb in the brain. Drugs deposited in the olfactory region can cross the epithelial barrier and reach the olfactory neurons. These drugs are then transported either intracellularly within neurons or extracellularly along the perineural channels. Once they reach the olfactory bulb, they can further distribute to different regions of the brain. This pathway is particularly advantageous because it bypasses the blood–brain barrier and allows direct access to the central nervous system.
However, the limited surface area of the olfactory region restricts the amount of drug that can be delivered through this pathway.¹⁹

4.2 Trigeminal Nerve Pathway

The trigeminal nerve pathway provides an additional route for drug transport from the nasal cavity to the brain. The trigeminal nerve innervates both the respiratory and olfactory regions of the nasal mucosa. Drugs absorbed in these regions can be transported along the trigeminal nerve branches to the brainstem and other parts of the central nervous system. This pathway enables drug delivery to deeper brain structures such as the pons and spinal cord. Compared to the olfactory pathway, the trigeminal pathway offers a broader distribution within the brain. It is especially important for drugs that do not efficiently utilize the olfactory route.²⁰

4.3 Intracellular vs Extracellular Transport

Drug transport from the nasal cavity to the brain occurs through both intracellular and extracellular mechanisms. Intracellular transport involves the uptake of drug molecules into olfactory or trigeminal neurons through endocytosis. Once inside the neurons, the drugs are transported along axons via axonal transport mechanisms. This process is relatively slow and may take several hours to days for drugs to reach the brain. Extracellular transport, on the other hand, occurs through the spaces between cells or along the perineural channels surrounding neurons. This mechanism allows faster movement of drugs to the brain, often within minutes. Extracellular transport is considered the dominant mechanism for rapid nose-to-brain delivery, while intracellular transport contributes to sustained drug delivery.^21,22,23

4.4 Systemic Absorption vs Direct Transport

Drugs administered intranasally can reach the brain through two main routes: systemic absorption and direct transport. In systemic absorption, drugs are absorbed into the bloodstream through the highly vascularized nasal mucosa. These drugs then circulate systemically and must cross the blood–brain barrier to reach the brain. This route is similar to conventional drug delivery and is limited by the restrictive nature of the blood–brain barrier. In direct transport, drugs bypass systemic circulation and are delivered directly to the brain via the olfactory and trigeminal nerve pathways. This route provides faster onset of action and reduces systemic side effects. The relative contribution of systemic versus direct transport depends on factors such as drug properties, formulation type, and site of deposition within the nasal cavity.²⁴

4. Factors Affecting Intranasal Drug Delivery

Intranasal drug delivery is influenced by a combination of physicochemical, formulation, biological, and patient-related factors that collectively determine drug absorption, bioavailability, and therapeutic efficacy. A clear understanding of these factors is essential for designing efficient nose-to-brain and systemic delivery systems.

1. 1. Physicochemical Properties of Drug

The physicochemical characteristics of a drug play a critical role in determining its absorption across the nasal mucosa. Molecular weight is one of the most important factors affecting nasal absorption.
Small molecules with a molecular weight less than 300–400 Da are readily absorbed through the nasal epithelium, whereas larger molecules exhibit poor permeability and often require carrier systems. Lipophilicity significantly influences transcellular transport across the nasal epithelium. Drugs with moderate lipophilicity show enhanced membrane permeability and improved absorption, while highly hydrophilic drugs rely on limited paracellular pathways. Solubility is another key determinant of drug absorption. Drugs must be sufficiently soluble in the nasal mucus to be available for absorption, but excessive hydrophilicity may reduce membrane permeability. The degree of ionization of a drug, which depends on its pKa and the pH of the nasal environment, also affects its absorption. Unionized forms of drugs are generally more permeable across biological membranes compared to ionized forms.^25,26

1. 2. Formulation Factors

Formulation parameters play a significant role in enhancing or limiting drug delivery through the nasal route. The pH of the formulation should be compatible with the physiological pH of the nasal cavity, which typically ranges from 4.5 to 6.5. Maintaining an appropriate pH helps prevent nasal irritation and ensures drug stability and solubility. Viscosity of the formulation affects the residence time of the drug in the nasal cavity. Higher viscosity formulations, such as gels and mucoadhesive systems, can prolong contact time with the nasal mucosa and enhance drug absorption. However, excessively viscous formulations may interfere with ciliary movement and reduce drug diffusion. Osmolarity is another important factor influencing nasal drug delivery. Isotonic formulations are generally preferred because they maintain mucosal integrity and prevent irritation. Hypertonic or hypotonic formulations can cause nasal discomfort, alter mucociliary clearance, and reduce drug absorption.²⁷

1. 3. Biological Factors

Biological factors within the nasal cavity can significantly influence drug absorption and bioavailability. The presence of mucus acts as both a protective and restrictive barrier. While mucus traps foreign particles and pathogens, it can also limit drug diffusion and reduce the amount of drug reaching the epithelial surface. Mucociliary clearance is a dynamic process that continuously removes mucus and entrapped substances from the nasal cavity. This mechanism reduces the residence time of drugs and can lead to decreased absorption. Enzymatic activity in the nasal mucosa is another critical factor. Various enzymes, including proteases and cytochrome P450 enzymes, can degrade drugs before they are absorbed. This is particularly important for peptide and protein drugs, which are highly susceptible to enzymatic degradation.²⁸

1. 4. Patient-Related Factors

Patient-related factors can also influence the effectiveness of intranasal drug delivery. Physiological variations such as age, gender, and health status can affect nasal absorption. For example, children and elderly individuals may exhibit differences in mucociliary clearance and nasal physiology. Pathological conditions such as rhinitis, sinusitis, and nasal congestion can significantly alter drug absorption. Inflammation may increase permeability in some cases, while excessive mucus production can hinder drug diffusion. The technique of administration is another important factor. Improper positioning or incorrect use of nasal delivery devices can result in poor drug deposition and reduced efficacy. Environmental factors such as temperature and humidity may also influence nasal physiology and drug absorption.²⁵

5. Nanocarrier-Based Drug Delivery Systems

Nanocarrier-based systems have emerged as a promising strategy for intranasal drug delivery to the brain due to their ability to bypass the blood–brain barrier (BBB), enhance drug stability, improve bioavailability, and enable targeted delivery via olfactory and trigeminal pathways.²⁹

1. 1. Liposomes

Liposomes are spherical vesicular systems composed of one or more phospholipid bilayers enclosing an aqueous core, typically ranging from nanometers to micrometers in size.

They possess the unique ability to encapsulate both hydrophilic drugs within the aqueous core and lipophilic drugs within the lipid bilayer, making them highly versatile carriers.  Liposomes are biocompatible, biodegradable, and capable of protecting drugs from enzymatic degradation in the nasal cavity while prolonging residence time.  In intranasal delivery, liposomes facilitate drug transport to the brain via olfactory and trigeminal nerve pathways, either directly or after systemic absorption. Furthermore, surface-modified liposomes (e.g., chitosan-coated or PEGylated) enhance mucoadhesion and improve targeting efficiency to specific brain regions.³⁰

1. 2. Nanoparticles

Polymeric Nanoparticles

Polymeric nanoparticles are colloidal systems made from biodegradable polymers such as PLGA, chitosan, and PEG, designed to encapsulate drugs and control their release. These nanoparticles enhance drug permeability across the nasal epithelium and improve brain targeting through sustained release and mucoadhesive properties. Additionally, polymeric nanoparticles protect drugs from enzymatic degradation and improve stability during nasal administration.³¹

Solid Lipid Nanoparticles (SLNs)

Solid lipid nanoparticles are composed of solid lipids stabilized by surfactants and represent a promising system for nose-to-brain delivery. They provide controlled drug release, improved stability, and enhanced penetration across biological barriers due to their lipidic nature.  SLNs also reduce drug toxicity and improve bioavailability by facilitating transport across the BBB and nasal mucosa.³¹

Nanostructured Lipid Carriers (NLCs)

Nanostructured lipid carriers are second-generation lipid nanoparticles composed of a mixture of solid and liquid lipids. This structure creates imperfections in the lipid matrix, allowing higher drug loading capacity and preventing drug expulsion during storage. NLCs offer improved stability, better targeting efficiency, and enhanced therapeutic outcomes in brain delivery via the intranasal route.³²

Nanoemulsions

Nanoemulsions are thermodynamically or kinetically stable dispersions of oil and water stabilized by surfactants, with droplet sizes typically in the nanometer range. They improve drug solubility, especially for poorly water-soluble drugs, and enhance absorption across the nasal mucosa. Nanoemulsions also increase drug permeability and bioavailability while providing a large surface area for rapid drug transport to the brain.³²

1. 3. Dendrimers

Dendrimers are highly branched, tree-like macromolecules with a well-defined structure and multiple functional surface groups. These nanocarriers enable precise drug targeting due to their multivalency and ability to conjugate ligands or targeting moieties. Dendrimers enhance drug solubility, permeability, and controlled release, making them suitable for intranasal brain delivery applications.

1. 4. Micelles

Micelles are self-assembled colloidal structures formed by amphiphilic molecules, consisting of a hydrophobic core and hydrophilic shell.

They are particularly useful for solubilizing poorly water-soluble drugs and improving drug stability in biological environments. Micelles facilitate drug transport across the nasal epithelium and enhance delivery to the brain via transcellular pathways.

1. 5. Hybrid Systems (Lipid–Polymer Hybrid Nanoparticles)

Hybrid nanoparticles combine the advantages of both polymeric and lipid-based systems, typically consisting of a polymeric core surrounded by a lipid shell. This structure provides improved stability, controlled drug release, and enhanced biocompatibility compared to conventional nanoparticles. Lipid–polymer hybrid nanoparticles also enhance drug encapsulation efficiency and targeting capability, making them highly effective for intranasal brain delivery.³³

6. Targeting Strategies and Surface Modifications

Targeting strategies and surface modifications play a crucial role in enhancing the efficiency of intranasal drug delivery systems, particularly for brain targeting. These approaches are designed to improve drug stability, prolong nasal residence time, enhance permeability across biological barriers, and facilitate selective delivery to specific sites within the central nervous system. Surface modification of drug carriers, especially nanocarriers, has emerged as an effective strategy to overcome physiological and anatomical barriers associated with nose-to-brain delivery.

7.1 Ligand-Based Targeting

Ligand-based targeting involves the attachment of specific ligands to the surface of drug carriers to enable selective interaction with receptors present on the nasal epithelium or neuronal pathways.
This approach enhances cellular uptake and facilitates targeted drug delivery to the brain. Lectins are carbohydrate-binding proteins that can selectively bind to sugar moieties present on the mucosal surface. When used as targeting ligands, lectins can improve adhesion to the nasal mucosa and promote uptake through receptor-mediated endocytosis. This results in enhanced drug transport across the nasal epithelium and improved brain targeting efficiency. Antibodies are highly specific ligands that can bind to particular receptors expressed on epithelial or neuronal cells. Surface modification of nanocarriers with antibodies allows for receptor-mediated targeting, leading to increased uptake and selective delivery of drugs to desired sites. This strategy is particularly useful for targeting specific brain regions or pathological sites.³⁴

1. 2. PEGylation

PEGylation refers to the attachment of polyethylene glycol (PEG) chains to the surface of drug molecules or nanocarriers. This surface modification technique is widely used to improve the pharmacokinetic and pharmacodynamic properties of drug delivery systems. PEGylation enhances the hydrophilicity of drug carriers, which reduces aggregation and improves their stability in biological environments. It also provides a steric barrier that protects drug carriers from enzymatic degradation and recognition by the immune system. In the context of intranasal delivery, PEGylation can help reduce mucociliary clearance by minimizing interactions with mucus components. This leads to prolonged residence time in the nasal cavity and increased opportunities for drug absorption. Additionally, PEGylated carriers may exhibit improved diffusion through the mucus layer due to reduced adhesion to mucin fibers.³⁵

1. 3. Mucoadhesive Polymers

Mucoadhesive polymers are widely used in intranasal formulations to enhance drug retention and absorption. These polymers interact with the mucus layer, increasing the residence time of drugs in the nasal cavity. Chitosan is a natural, cationic polymer derived from chitin that exhibits excellent mucoadhesive properties. It can interact with negatively charged sialic acid residues in mucus, leading to strong adhesion to the nasal mucosa. Chitosan also has the ability to transiently open tight junctions between epithelial cells, thereby enhancing paracellular drug transport. This makes it particularly useful for the delivery of hydrophilic drugs and macromolecules. Carbopol is a synthetic, high molecular weight polymer that exhibits strong mucoadhesive and gel-forming properties. It can swell in aqueous environments, forming a viscous gel that prolongs drug residence time in the nasal cavity.³⁵
 

7. Applications in Brain Disorders³⁶

Intranasal drug delivery systems have gained significant attention for the treatment of central nervous system (CNS) disorders due to their ability to bypass the blood–brain barrier (BBB) and deliver drugs directly to the brain via olfactory and trigeminal pathways. These systems, particularly when combined with nanocarriers, enhance drug bioavailability, reduce systemic side effects, and improve therapeutic outcomes in various neurological disorders.

1. 1. Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and accumulation of amyloid-β plaques in the brain. Conventional drug delivery approaches are limited due to poor penetration across the BBB and rapid systemic metabolism. Intranasal drug delivery offers a promising alternative by enabling direct transport of therapeutic agents to the brain, thereby improving drug concentration at the target site. Nanocarrier-based systems such as nanoemulsions, liposomes, and nanostructured lipid carriers (NLCs) have shown enhanced brain targeting, improved drug stability, and reduced toxicity in Alzheimer’s therapy. Additionally, intranasal delivery of drugs such as rivastigmine, donepezil, and insulin has demonstrated improved cognitive function in preclinical and clinical studies.

1. 2. Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disorder associated with the loss of dopaminergic neurons and reduced dopamine levels in the brain. The major challenge in Parkinson’s therapy is the inability of most drugs to effectively cross the BBB, resulting in limited therapeutic efficacy. Intranasal drug delivery has emerged as an effective strategy for delivering anti-Parkinsonian drugs directly to the brain, thereby bypassing the BBB and improving drug bioavailability. Various nanocarriers such as polymeric nanoparticles, nanoemulsions, liposomes, and nanomicelles have been explored for intranasal delivery of drugs like levodopa and dopamine agonists. These systems enhance drug targeting, prolong drug residence time in the nasal cavity, and provide sustained drug release, leading to improved therapeutic outcomes.

1. 3. Brain Tumors

Brain tumors, including glioblastoma, present significant challenges in drug delivery due to the restrictive nature of the BBB and tumor microenvironment. Conventional chemotherapy is often ineffective due to poor drug penetration into the brain and systemic toxicity. Intranasal delivery of chemotherapeutic agents using nanoparticles has shown potential in improving drug accumulation in brain tumor tissues. Nanocarriers such as solid lipid nanoparticles, polymeric nanoparticles, and lipid–polymer hybrid systems enhance drug targeting, reduce toxicity, and improve therapeutic efficacy in brain tumor treatment. Furthermore, targeted nanocarriers functionalized with ligands enable site-specific delivery to tumor cells, increasing treatment efficiency.

1. 4. Epilepsy

Epilepsy is a chronic neurological disorder characterized by recurrent seizures due to abnormal neuronal activity in the brain. Many antiepileptic drugs suffer from poor brain targeting and systemic side effects when administered orally or intravenously. Intranasal drug delivery provides rapid onset of action and direct drug transport to the brain, making it highly suitable for emergency seizure management. Nanocarrier-based systems such as nanoemulsions and nanoparticles enhance drug absorption, improve bioavailability, and provide sustained drug release in epilepsy treatment. Intranasal formulations of drugs like diazepam and midazolam have demonstrated improved seizure control and faster therapeutic action.

1. 5. CNS Infections

Central nervous system infections, including meningitis and encephalitis, require effective drug delivery to the brain for successful treatment. However, the BBB significantly restricts the entry of antimicrobial agents, leading to inadequate drug concentrations at the site of infection. Intranasal drug delivery offers a non-invasive route to deliver antimicrobial drugs directly to the brain, thereby enhancing therapeutic efficacy. Nanocarrier systems such as liposomes and nanoparticles protect drugs from degradation and facilitate their transport across nasal and brain barriers. Additionally, intranasal delivery reduces systemic toxicity and improves patient compliance in the treatment of CNS infections.

Conclusion

Intranasal drug delivery represents a promising non-invasive approach for brain targeting by bypassing the blood–brain barrier through olfactory and trigeminal pathways, enabling rapid and direct drug transport to the CNS. However, challenges such as mucociliary clearance, enzymatic degradation, and limited epithelial permeability can restrict its efficiency.

Advances in nanotechnology have significantly improved this approach. Nanocarriers like liposomes, nanoparticles, and nanoemulsions enhance drug stability, prolong nasal residence time, enable controlled release, and improve targeting efficiency. Additionally, surface modifications such as PEGylation, ligand conjugation, and mucoadhesive polymers help overcome biological barriers and enhance drug absorption.

These systems show strong potential in treating CNS disorders, including neurodegenerative diseases, brain tumors, epilepsy, and infections, by improving therapeutic outcomes while reducing systemic side effects. Overall, intranasal nanocarrier-based delivery offers an effective platform for brain targeting, though further research is needed for clinical translation and large-scale application.

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