Available online on 15.11.2025 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2025 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access Full Text Article                                                Review Article

Intranasal nanoparticulate drug delivery systems for neurodegenerative disorders: an Overview

Poonam Sahu ¹, Trilochan Satapathy ¹* , Shiv Kumar Bhardwaj ¹ , Abinash Satapathy ² , Abhisek Satapathy ³ , Arvind Kumar ⁴, Manoj Kumar ⁵, Princy Kashyap ⁵, Kunal Chandrakar ⁶ , Manisha Chandrakar ⁶

¹ Columbia Institute of Pharmacy, Vill-Tekari, Near Vidhansabha, Raipur-493111, C.G., India

² College of Veterinary Science and Animal Husbandry, Anjora, Durg, 491001, C.G, India

³ Pt J.N.M. Medical College, Railway Station Rd, Moudhapara, Raipur-492001, C.G., India

⁴ Faculty of Pharmacy, Kalinga University, Kotni, Naya Raipur-492001, C.G., India

⁵ Department of Pharmacy, Guru Ghasidas Central University, Koni, Bilaspur-495009, C.G., India

⁶ University College of Pharmacy, CSVTU, Bhilai-491107, C.G., India

 

 

1. Introduction: 

Four decades ago (during 1980s) intranasal route was introduced to systemic deliver of some therapeutic agents as an alternative to conventional drug delivery systems.¹In ancient Ayurvedic literature of Indian medicinal system, intranasal route was described as “Nasya Karma”. ² According to advancement of science and drug discovery, intranasal route is considered as a promising route by the researchers for delivery of different therapeutic agents targeted to lungs, brain etc. in the form of nanoparticulate drug delivery systems which possess several unique advantages over other conventional dosage forms that align well with the properties of nanoparticles and the physiological features of the nasal cavity. ³ The nasal cavity is in close proximity to the brain, and intranasal administration allows the therapeutic agents to bypass the blood-brain barrier (BBB), which is generally a major challenge in drug delivery for various CNS related disorders.⁴The major advantage to choose the intranasal route as it is structured with porous endothelial membrane and possess dense network of blood vessels which provides a quick and rapid absorption of therapeutic agents into the systemic circulation thereby enhance the solubility, stability, and bioavailability of drugs that can lead to a more effective therapeutic response.⁵ Nanoparticulate delivery can facilitate the transport of various therapeutic agents directly to the brain through olfactory and trigeminal nerves, making the nasal route especially useful for different neurological disorders such as Alzheimer's, Parkinson's, and brain tumors etc. ⁶ Intranasal drug delivery is non-invasive, pain-free, and easy to administer, which is a significant advantage over other parenteral routes like injection thereby improve patient compliance, especially in chronic treatments or pediatric and elderlypopulations.⁷Many challenges such as controlling the release of active drugs are observed during the development of a delivery system.⁸ Nanoparticulate delivery system can be structured to control the release pattern of the drug, allowing it to exert sustained or prolonged drug action.⁹ Additionally, nanoparticles can develop to be functionalized to target specific organs or proteinaceous macromolecules of tissues, rely on several strategies and principles that facilitate the targeted accumulation, penetration, and internalization of nanoparticles at the desired site thereby enhancing the therapeutic efficacy and reducing side effects(commonly observed with oral or intravenous administration).¹⁰ In addition to systemic drug delivery, nanoparticles administered via intranasal route can also be used for localized treatment of diseases affecting the nasal and respiratory tract, such as infections, allergies, and inflammation.¹¹Nanoparticle can protect sensitive drugs (like proteins, and nucleic acids) from degradation by enzymes in the nasal cavity. These contributions make the nasal route ideal for precision medicine. Nanoparticles can be structured in such a manner to enhance their ability to penetrate the nasal mucosa and reach systemic circulation or target tissues more efficiently. ¹² The smaller size of nanoparticle allows them to pass through tight junctions between cells in the nasal epithelium, facilitating rapid absorption.¹³Another important mechanism for nanoparticulate drug delivery system is enhanced Permeability and retention (EPR) Effect, here, the mechanism exploits the leaky vasculature present in certain pathological tissues (like tumors) and the lymphatic system, allowing nanoparticles to accumulate more readily in these areas.  This phenomenon is referred to as the EPR effect of nanoparticulate delivery system.¹⁴ To exploit nanoparticulate EPR effect, the nanoparticles should be constructed with smaller sized particles (under 100 nm) and surface modifications such as PEGylation (coating with polyethylene glycol) etc. These properties of nanoparticles can enhance the circulation time and help to prevent premature clearance by the immune system.¹⁵

 

 

 

Figure 1: Graphical Abstract 

 

2. Ideal Characteristics of intranasal nanoparticles:

2.1 Particle size and surface architecture: Intranasal nanoparticles are considered as an innovative drug delivery system because it offers a non-invasive route for drugs to bypass the gastrointestinal system and the blood-brain barrier (BBB).¹⁶ For optimal performance, intranasal nanoparticles must have several ideal characteristics. The first and foremost characteristics particle size that should range between 100-500 nm in diameter. ¹⁷ Particle size above 500 nm may be trapped in the nasal mucosa.^18-19 Smaller sized particles may penetrate the mucus more easily and have a larger surface area for interaction. ²⁰ Thus, an optimal size range is critical for prolonged retention. Similarly, surface architecture of nanoparticles is also of similar importance. The surface charge of nanoparticles can influence their interaction with the nasal mucosa.²¹ Neutral to slightly positive charges are often preferred to ensure good mucoadhesion without causing irritation. ²² Cationic particles tend to interact more effectively with the negatively charged mucosal membranes but may also cause toxicity if used in high concentrations. Surface properties, such as roughness and hydrophobicity/hydrophilicity balance, also affect mucoadhesion. ²³ Hydrophilic particles are generally more mucoadhesive because they tend to form stronger interactions with the mucus compared to hydrophobic particles. ²⁴The surface of nanoparticles can be modified with ligand or coatings (e.g., PEGylation, chitosan, or surfactants) to enhance mucoadhesion, drug release, and targeting. ²⁵

2.2 Mucoadhesion property of intranasal nanoparticles: Mucoadhesion property of a nanoparticleis crucial for prolonging the residence time at the nasal mucosa and ensuring sustained drug release. ²⁶ This can be achieved by incorporating biocompatible polymers like chitosan or poloxamers, which enhance adhesion to the mucosal surfaces and prevent rapid clearance. ²⁷ Considering the anatomical architecture, the nasal mucosa consisting mucus layer which is negatively charged due to the presence of glycoproteins (such as mucins), while the polymeric nanoparticles often have a positive charge (when cationic polymers are used). ²⁸This situation creates attractive electrostatic interactions between the nanoparticles and the mucosal surface, facilitating adhesion. In some circumstances polymeric nanoparticles could form hydrogen bonds with the hydroxyl, carboxyl, and amino groups in the mucus layer. ²⁹ This interaction helps improve the adhesion of the particles to the mucosal surface. Vander Waals Forces between the nanoparticles and mucus layer of nasal cavity are weaker but still significant forces that contribute to the adhesion between the nanoparticles and the mucosal layer.³⁰ Some specific polymer such as chitosan, are hydrophilic in nature and tend to swell when come in contact with the aqueous mucus layer.³¹ This swelling property can increase the surface area of the nanoparticles, enhancing the contact time with the mucosal surface and enhances therapeutic effectiveness of a nanoparticle formulations.³²  The polymeric nanoparticles sometimes undergo interpenetration with the mucus gel layer, where the polymer chains present in the nanoparticles intertwine with the mucus, leading to form a stronger bond.³³ This entanglement improves the stability of the particles at the site of deposition. Sometimes Polymeric nanoparticles are modified by coating with specific bio-adhesive polymers, such as chitosan or thiolated polymers, thereby improve their interaction with the mucus and hence better mucoadhesion.³⁴The viscosity of the nanoparticle formulation greatly influences how strongly the nanoparticles can interact with and penetrate the mucus.^35-36Formulations that are too viscous may affect nanoparticle movement, while those that are too fluid may not stay in contact with the mucosa long enough for effective drug delivery.^37-38Some environmental factors of nasal mucosa also affect the mucoadhesion of nanoparticle formulations. The pH of the nasal cavity and the ionic strength of the mucus also affect the degree of ionization of the polymers and the properties of the mucus. For example, pH changes may alter the charge on the nanoparticles and mucins, influencing their interaction.^39-40 In some specific circumstances, the ionic strength of the environment can also affect the viscosity of the mucus and influence the ability of nanoparticles to adhere to the mucosal surface.⁴¹

2.3 Controlled Release characteristics of nanoparticle: Controlled release of nanoparticles are considered as an essential factor to maintain therapeutic levels over an extended period of time as well as reducing the need for frequent dosing.^42-43 The drug is encapsulated in a nanoparticle matrix, and its release is governed by the diffusion of the drug molecules from the interior of the nanoparticles to the surrounding environment (nasal mucus).⁴⁴ In such circumstances, the drug molecules move from regions of high concentration (inside the nanoparticle) to regions of low concentration (the mucosal layer).⁴⁵Smaller nanoparticles typically have a larger surface area to volume ratio, which can lead to faster initial drug release.^46-47 However, for controlled release, nanoparticles are often designed with a size that allows for a slower diffusion process.When the nanoparticles are made from biodegradable or bio-responsive polymers (e.g., PLGA, chitosan), the polymer matrix slowly degrades, allowing for a gradual release of the drug. Lipophilic drugs often require surfactants or encapsulation in specific polymer matrices to control their release, as their diffusion can be slower than hydrophilic drugs.^48-49 Some polymeric nanoparticles, such as hydrophilic polymers, absorb water from the mucus layer, causing them to swell. ⁵⁰ The swelling process can lead to the gradual release of the encapsulated drug as the nanoparticle matrix becomes more porous, allowing the drug to diffuse out.^51-52 Hydrophilic polymers, like chitosan, are known to swell when they come into contact with water, which helps to release the encapsulated drug gradually. ^53-54The hydration and composition of the mucus also affect the swelling behavior of the nanoparticles, influencing the release rate. If the nanoparticles are made from biodegradable polymers (e.g., poly(lactic-co-glycolic acid) [PLGA], chitosan), the matrix can gradually degrade or erode over time.⁵⁵ As the polymer matrix breaks down, the encapsulated drug is released in a controlled manner. ⁵⁶The degradation rate of the polymer is critical to controlling the release rate. For instance, a slower degradation rate will result in a prolonged release of the drug. The degradation can occur through hydrolysis, enzymatic breakdown, or oxidation, depending on the type of polymer. ⁵⁷The nasal mucosal environment has a slightly acidic pH (around 5.5-6.5), and polymers can be designed to degrade in response to pH changes.⁵⁸pH-sensitive polymers will degrade faster or slower depending on the local pH, allowing for site-specific drug release.⁵⁹Polymers like poly(ethylene glycol) (PEG), polyacrylic acid, and other ionizable polymers can be used to design nanoparticles that release their contents in response to pH fluctuations.⁶⁰The nasal mucosa has a slightly acidic pH, and pH-sensitive formulations can exploit this characteristic to trigger drug release only when they come into contact with the mucus. ⁶¹Thermo sensitive polymers, such as poly(N-isopropylacrylamide) (PNIPAM), can be used in the formulation of nanoparticles that release the encapsulated drug in response to temperature changes. ⁶² Upon exposure to the nasal mucosa, a slight temperature change can trigger a change in the nanoparticle structure (e.g., from a gel state to a sol state), leading to the release of the drug. ^63-64 In some cases, nanoparticles are designed to release drugs through ion-exchange mechanisms or electrostatic interactions with the mucosal surface.⁶⁵ For example, anionic nanoparticles may release their drug payload through exchange reactions with the cations (e.g., calcium ions) in the mucus.⁶⁶ The electrostatic interaction between charged nanoparticles and the mucus can affect the release rate. ⁶⁷ The drug may be tightly bound to the nanoparticles through ionic interactions, and the release is controlled by the strength of these interactions.⁶⁸ Changes in the ionic strength of the mucus (e.g., due to inflammation or infection) can influence the release rate by altering the electrostatic interactions between the nanoparticles and the mucosal layer.^69-70 Some nanoparticles are designed to be susceptible to enzymatic degradation. ⁷¹ Enzymes present in the nasal mucosa, such as mucosal or digestive enzymes, can break down the polymer matrix or degrade the drug itself, leading to a controlled release. ⁷² The nanoparticle matrix can be engineered to contain specific linkages (e.g., ester or peptide bonds) that are cleaved by enzymes.⁷³ The release rate is dependent on the concentration and activity of the enzymes in the nasal mucosa.⁷⁴

 

 

 

Figure 2: Factors affecting the controlled release of intranasal Nanoparticles

 

2.4 Rapid onset and extended duration: Rapid onset and extended duration of a nanoparticulate delivery system is required in some emergency conditions like pain management or migraine etc that involve a combination of physical, chemical, and surface modification strategies during nanoparticle development. ^75-76Attaching specific ligands, antibodies, or peptides to the nanoparticle surface can enhance their ability to quickly interact with specific biological targets or environmental factors.⁷⁷ For example, attaching antibodies or cell-specific ligands can speed up the delivery of drugs to specific tissues. ⁷⁸Modifying the surface charge of nanoparticles (positively or negatively) can improve their interaction with biological membranes, improving uptake and accelerating the action of the nanoparticles. ^79-80The shape of nanoparticles can influence their movement and uptake.⁸¹ For instance, rod-shaped nanoparticles tend to enter cells faster compared to spherical ones, and some shapes are better suited for targeting specific tissues. ⁸²Incorporating stimuli-responsive materials, such as pH-sensitive, temperature-sensitive, or light-sensitive polymers, can make nanoparticles "triggered" to release their payload upon exposure to specific conditions. ^83-84 This allows for rapid release once they reach the target site. Utilizing core-shell nanoparticles with an outer layer that dissolves or degrades upon exposure to specific stimuli (like an acidic environment or enzymatic activity) can enhance rapid action once the particles arrive at the site of interest. Using mesoporous nanoparticles, such as mesoporous silica, allows for a higher loading capacity of active agents and facilitates a faster release. ^85-86 These materials are porous, which improves both drug loading and the rate at which the active substance is released. ⁸⁷Controlling aggregations of nanoparticles can be achieved by addition of anti-aggregation agents like surfactants or stabilizers which ensure that they maintain high surface area and don’t clump together.⁸⁸ Avoiding aggregation or clustering of nanoparticles within the system ensures that they remain active and can rapidly reach the target site. ⁸⁹High drug loading within nanoparticles improves the amount of active material available to be released, leading to a faster therapeutic effect.⁹⁰ Techniques like surface adsorption, encapsulation, or co-loading can be used to enhance drug loading capacity.⁹¹Modifying nanoparticles to facilitate faster diffusion through biological barriers (like the blood-brain barrier or cell membranes) can speed up their therapeutic action .^92-93 This could involve the use of surface coatings such as polyethylene glycol (PEG), which improves the solubility and bioavailability of nanoparticles.⁹⁴Encapsulating nanoparticles in biocompatible coatings (like liposomes or polymers) can enhance their stability and control the rate of payload release, thereby improving their overall efficacy and the speed at which they act once administered. ⁹⁵

3. Anatomy and Physiology of nasal route: 

The nasal cavity consists of several key structures that contribute to the absorption and distribution of intranasally delivered drugs, including nanoparticles.⁹⁶ The external opening of the nose, lined with skin and hair, which acts as a first line of defense against large particles and contaminants. ⁹⁷ The interior of the nasal cavity, which is divided into two nostrils by the nasal septum. ⁹⁸ The walls are lined with mucosa and hair, which help filter air and trap particles. ⁹⁹ These are three bony structures (superior, middle, and inferior turbinates) covered by mucosal tissue that help warm, moisten, and filter the air. ¹⁰⁰The turbinates create turbulent airflow, which allows the drug to interact more effectively with the mucosal surfaces. ¹⁰¹The lining of the nasal cavity consists of respiratory epithelium, which is rich in cilia (tiny hair-like structures) and goblet cells (that secrete mucus). ¹⁰² This mucosal layer plays an important role in drug absorption and clearance.¹⁰³ Located at the top of the nasal cavity, it is specialized for smell and is connected to the brain via the olfactory nerve. This region is significant for direct CNS delivery of drugs.¹⁰⁴ A sensory nerve that innervates the nasal mucosa and provides a pathway for drugs to enter the central nervous system, particularly via the trigeminal nerve to the brainstem. ^105-106 The mucosal layer in the nasal cavity is continuously bathed in mucus, which serves as a protective barrier.¹⁰⁷ The cilia on the epithelial cells move in a coordinated fashion to transport mucus (and trapped particles) toward the throat to be swallowed or expelled. ¹⁰⁸ This clearance mechanism is a challenge for drug delivery, but nanoparticulate systems can be engineered to resist rapid clearance by mucus. The nasal mucosa is generally more permeable than the gastrointestinal tract, allowing for faster and more efficient absorption of drugs.¹⁰⁹ However, the permeability can vary depending on the size, charge, and surface characteristics of nanoparticles. The nasal mucosa is highly vascularized, with a dense network of blood vessels (primarily capillaries), which aids the rapid absorption of drugs into the systemic circulation.¹¹⁰ Nanoparticles can exploit these vessels for systemic delivery after absorption. The olfactory epithelium and trigeminal nerve are connected directly to the brain. When nanoparticles are delivered intranasally, they have the potential to bypass the blood-brain barrier via these nerve pathways. This direct route to the CNS is particularly useful for treating neurological disorders. ¹¹¹

4. Transport of Intranasal Nanoparticles to CNS via Trigeminal Pathway: 

The trigeminal pathway involved in the sensory processing of stimuli from the face, including the nasal cavity. Intranasal administration of nanoparticles has become an increasingly popular method for delivering drugs to the central nervous system (CNS), as it can bypass the blood-brain barrier (BBB) and directly target the brain.¹¹² The trigeminal nerve has three main branches. Ophthalmic (V1): Carries sensory information from the forehead, scalp, and upper part of the nose. Maxillary (V2): Carries sensory information from the lower part of the nose, cheeks, and upper lip. Mandibular (V3): Carries sensory information from the jaw and chin. ¹¹³The trigeminal nerve has its cell bodies located in the trigeminal ganglion, and its axons project to the trigeminal nerve nuclei in the brainstem (specifically, the spinal trigeminal nucleus and the trigeminal sensory nucleus). Sensory input from the nasal cavity is particularly carried by the ophthalmic (V1) and maxillary (V2) branches. ¹¹⁴When nanoparticles are administered intranasally (via nasal spray or other delivery forms), they interact with the mucosal lining of the nasal cavity. The nanoparticles can be absorbed through the epithelial cells of the nasal mucosa. ¹¹⁵ Some of these particles will penetrate through the nasal epithelium and enter the trigeminal nerve endings present in the nasal mucosa, particularly in the upper parts of the nose (innervated by the ophthalmic and maxillary branches). ¹¹⁶Activation of Trigeminal Nerve occurs once the nanoparticles come into contact with the trigeminal nerve fibers in the nasal mucosa, they activate these sensory nerve endings.¹¹⁷ This can lead to direct transmission of the signal through the trigeminal nerve, either to the trigeminal ganglion or directly to the brainstem. From the trigeminal nerve, the signal is relayed to the brainstem and further sent to higher brain centers, such as the thalamus and cerebral cortex, for processing. ¹¹⁸The nanoparticles themselves may also be transported via the trigeminal nerve fibers to deeper regions of the brain, including the medulla and even the cerebellum.¹¹⁹ Nanoparticles may travel along the olfactory nerve and into the olfactory bulb, which directly connects to the brain, providing an efficient route for brain delivery bypassing the blood-brain barrier.¹²⁰ The trigeminal nerve can also relay particles directly into regions like the brainstem, cortex, and even into deeper structures like the medulla, which is associated with autonomic regulation. ¹²¹

5. Advantages of the Trigeminal Pathway for nanoparticulate drug delivery: 

Bypassing the Blood-Brain Barrier (BBB) is an important criterion for Intranasal nanoparticles that follow the trigeminal pathway offer a promising route for delivering drugs to the CNS without needing to cross the blood-brain barrier, a major challenge in drug development. ¹²²Since the trigeminal nerve is connected to several areas of the brainstem and higher brain regions, nanoparticles delivered through this pathway can potentially target specific regions, offering therapeutic benefits for conditions like neurological disorders, pain management, and CNS diseases.¹²³

 

 

Figure 3: Absorption of nanoparticulate delivery system via olfactory nerve and trigeminal nerves to CNS

 

6. Physiological and Pharmacological interaction of Nanoparticle with Nasal Physiology via olfactory System:

Nanoparticles interact with the nasal physiology through a combination of physical and chemical mechanisms, including their size, shape, surface charge, and fictionalization.¹²⁴ These interactions influence the absorption and transport of Nanoparticle through the nasal mucosa and into systemic circulation or the CNS.¹²⁵ The nasal cavity is lined with a mucosal layer, primarily composed of epithelial cells, cilia, and mucus, which serve as the first line of defense against foreign particles.¹²⁶ The olfactory epithelium (located in the upper nasal region) and the respiratory epithelium (in the lower and middle parts) both play important roles in the absorption and clearance of nanoparticles.¹²⁷Olfactory epithelium has specialized nerve endings (olfactory sensory neurons) that allow for direct neuronal transport to the brain whereas Respiratory epithelium is lined with cilia and goblet cells, produces mucus to trap and clear foreign particles.¹²⁸The ciliary movement helps to clear nanoparticles or prevent their deeper penetration into the nasal mucosa. Nanoparticles can pass directly through the epithelial cells or paracellularly between the cells, depending on their characteristics. ¹²⁸ It may be taken up by cells via mechanisms like phagocytosis (for larger particles) or pinocytosis (for smaller particles), allowing them to enter the bloodstream or reach deeper tissue.¹²⁹Nanoparticles that interact with the olfactory epithelium can directly travel along the olfactory nerve to the olfactory bulb, then spread to the brain.¹³⁰ As described earlier, nanoparticles may be absorbed through the trigeminal nerve fibers in the nasal mucosa, leading to direct CNS targeting.¹³¹ The surface properties (e.g., charge, hydrophobicity, and functionalization) influence the interaction with nasal epithelial cells and the subsequent release and distribution of the drug into the brain.¹³²Nanoparticle surface modification such as PEGylation reduces particle clearance by the immune system and prolongs circulation time. Receptor-targeting ligands can enhance site-specific delivery to brain tissues or other targets. ¹³³

7. Pharmacokinetic of Intranasal nanoparticles: 

The nasal mucosa is highly vascularized, allowing for the rapid absorption of drugs and nanoparticles. The drug particles are typically absorbed through the epithelial cells lining the nasal cavity.¹³⁴ Nanoparticles, owing to their small size and large surface area, can easily permeate the mucosal barrier and enter systemic circulation or reach the central nervous system (CNS).After absorption through the nasal mucosa, nanoparticles can enter the systemic circulation via the blood vessels of the nasal cavity. ¹³⁵ The nasal route offers the advantage of bypassing the gastrointestinal tract and hepatic first-pass metabolism, which can lead to higher bioavailability compared to oral administration.¹³⁶Depending on the formulation (e.g., lipid-based, polymeric, or protein-based nanoparticles), the distribution of nanoparticles can be influenced by their physicochemical properties, such as surface charge, hydrophobicity, and size.¹³⁷Once in the bloodstream, nanoparticles can be subjected to metabolism by liver enzymes, but they can also avoid hepatic first-pass metabolism due to their direct entry into systemic circulation.¹³⁸ The metabolic fate of nanoparticles depends on their material composition, and some may be metabolized to release the encapsulated drug or degrade into smaller components.¹³⁹Certain nanoparticles (e.g., biodegradable ones) may degrade over time, releasing their therapeutic payloads as they are broken down by enzymes or under physiological conditions. The degradation products can be further metabolized by the liver or other organs, and eventually excreted from the body.¹⁴⁰Nanoparticles that do not undergo metabolism may be eliminated via the kidneys. The size and surface properties of nanoparticles significantly affect their renal clearance.¹⁴¹Smaller nanoparticles (below 10 nm) are more likely to be excreted through the kidneys, while larger nanoparticles may undergo phagocytosis by the reticuloendothelial system (RES) in the liver and spleen.¹⁴²Larger nanoparticles may be cleared via the bile and excreted in the feces. The composition of the nanoparticles affects their route of excretion, with some formulations favoring biliary clearance over renal.¹⁴³

8. Pharmacodynamics of intranasal Nanoparticle: 

Intranasal nanoparticulate drug delivery systems provide a novel approach for enhancing drug efficacy, particularly for central nervous system (CNS) disorders, by facilitating targeted drug delivery.¹⁴⁴Upon intranasal administration, nanoparticles cross the olfactory epithelium/trigeminal nerve distributing the drug to different brain regions. Once distributed, Nanoparticles release the content that act on specific receptors, modulating neurotransmission and cellular responses. ¹⁴⁵Many CNS-active drugs (e.g., dopamine agonists, serotonin reuptake inhibitors) regulate neurotransmitter levels to exert their effects.¹⁴⁶ Drug-loaded Nanoparticle can target receptors such as NMDA, GABA, or opioid receptors, leading to neuro modulatory effects.¹⁴⁷Some Nanoparticles facilitate direct intracellular drug delivery, enhancing therapeutic action at the molecular level.¹⁴⁸ InAlzheimer’s disease, intranasal nanoparticles enhance brain uptake of neuroprotective agents like curcumin or rivastigmine, reducing amyloid-beta accumulation and oxidative stress.¹⁴⁹ For the treatment of Parkinson’s disease, intranasal nanoparticles containing bio-molecules that interact with dopaminergic pathway and help to restore dopamine levels in the substantia nigra, improving motor control. Intranasal SSRIs or neuropeptides (e.g., oxytocin) exert rapid antidepressant and anxiolytic effects by modulating serotonin or oxytocin receptors.¹⁵⁰

 

 

Table1. List of suitable drug candidates for intranasal nanoparticulate delivery

S.No	Drug	Polymer	Method of Production	Particle size	Zeta Potential	Entrapment efficiency (%)	Outcome	Ref
1.	Estradiol	Chitosan NP	Ionic interaction-prepared lipid nanocarriers	269.3±31.6	+25.4	64.7%	The concentrations of estradiol-loaded NPs were quite high	151
2	Rivastigmine	Chitosan with tween 80	Polymeric nanoparticles prepared using ion gelation method	163.7±7.6nm	45.30±6.21 mV	85.3 %	Significant drug loading was seen using chitosan nanoparticles, with reduced accumulation in the liver, spleen, and heart.	152-153
3	Donepezil	Lutrol F127/Carbapol 934	Melt emulsification high pressure hmozenization	112.5±2.44 nm	-23.2mV	98.7±4.01%	Brain concentration is higher than that of the free drug.	154
4	Curcumin	Lactoferrin	Desolvation method	84.8±6.5nm	+22.8±4.3mV	248.1%	When compared to free curcumin, the permeability of curcumin nanoparticles was significantly enhanced.	155
5	Caffeic acid	transferrin	Liposome	139±9nm	±56.30	23±4%	There was disaggregation activity against the Aβ42 peptide by Tf-CA liposomes.	156
6	Rhein and Polydopamine	Fe-Rh/Pda NPs	Metal nanoparticles	75.14±173	-2.27 – (-10.5mv)	27.71±6.86	Rhein was more bioavailable to the brain when encased in nanoparticles than was administered alone.	157
7	Galantamine	Chitosan/ Chitosan alginate complex NP	Ionotropic gelation	240nm	+58mv	67%	Prolonged release. There was no significant neurotoxicity caused by the new formulation.	158
8	Tacrine	Poly (n-butyl cyanoacrylate) with polysorbate 80	Lipid nanocarriers synthesized via emulsion polymerization	117.4nm	-10.0±0.9	22%	Compared to free tacrine and uncoated nanoparticles, tacrine concentrations in the brain were shown to be higher when poly (n-butyl cyanoacrylate) nanoparticles were coated with 1% polysorbate 80.	159
9	Doxorubicin	Stealth (PEG2000) and non-stealth SLN	Lipid nanocarriers synthesized via high-pressure homogenization	118±0.92	+22.5±8.68	38.40±8.94	The outcome is a higher doxorubicin concentration.	160
10	Curcumin	mannose	Liposome	100nm	-3.6±4.3	94.23±2.886	The absorption and accumulation of curcumin liposomes in N2a cells were enhanced.	161
11	Estradiol	Polylactide-co-glycolide (PLGA) with tween 80	Polymeric nanoparticles	98.3±2.6	78.9±2.1	51.34±5.59	Compared to free drugs, coated nanoparticles demonstrated superior brain absorption.	162
12	RHT (Rivastigmine Hydrogen Tartrate)	Eudragit RL100	nanoprecipitation	118±0.92	+22.5±8.68	38.40±8.94	Nanoparticles of eudragit loaded with RHT have the potential to increase nasal bioavailability by effectively adhering to the nasal surface.	163
13	Simvastatin	Simvastatin-Loaded PCL (poly-ε-caprolactone	Nanocapsules	202.5±18.0	-22.2±3.2	99.8±0.7	Prepared NPs demonstrated great bioavailability and shorter delivery times.	164
14	Simvastatin	Simvastatin loaded Lecithin/chitosan nanoparticles	Nanoparticles	212.6±7.2	+40.4±2.1	99.3±1.1	Prepared NPs demonstrated great bioavailability and shorter delivery times.	165
15.	Buspirone HCL	BUH thiolated chitosan	Ion gelation	226.7±2.52nm	+39.2±3.1	81.13±2.8	Higher concentration in brain.	166
16	Agomelatine	Agomelatine with PLGA	NPs	167.70±0.42nm	-17.90mv±2.70	91.25±1.70%	Absolute bioavailability and brain delivery of agomelatine were both greatly enhanced by intranasal injection of solid lipid nanoparticles.	167
17	Duloxetine	Duloxetine nanostructured lipid carriers	Lipid carriers	265.13±9.85	2.79±0.44mV	98.13±0.50%	Better brain targeting & decreased side effects	168
18	Folic acid		Niosomes	3.05–5.625		69.42%	High absorption through nasal cavity	169
19	selegiline	Chitosan	Selegiline Hydrochloride thiolated chitosan NPs	186±21.45	70±2.71	215±34.71	Attenuation of the oxidative stress and restoring the mitochondrial complex activity	170
20	Venlafaxine	Alginate	Venlafaxine alginate NPs	173.7±2.5	37.50±1.74	81.3±1.9	More enhanced excellent brain/blood ratios	171
21	Aripiprazole	Gellan gum (APZ-TFS-Gel )	Transferosome by using ion triggered deacetylation	72.12±0.72nm	-55.56±1.9mv	97.06±0.10%	Higher systemic and brain bioavailability	172
22	Haloperidol	GMS,compritol ATO 888, precirol ATO 5	Solid lipid nanoparticles using Modified emulsification-diffusion technique	115.1±2.78	-16.7	71.56±1.56	Increased haloperidol concentrations in brain tissue as compared to free drug	173
23	Lurasidone	Oil (Camptex 335EP, Capryol 90)	Nanoemulsion prepared using high pressure homogenization	48.07±3.29	-0.20±0.01	97.87±0.702%	Increased concentrations of Lurasidone in brain	174
24	Huperzine A (Huperzia serrata)	Lactoferrin conjugatedN-trimethylated chitosan	NPs were prepared using emulsion solvent evaporation	153.2±13.7nm	+35.6±5.2mV	73.8±5.7	Better permeability	175
25	Rutin	chitosan	NPs prepared using Inotropic gelation	85-100nm	_	_	Better permeability than oral administration	176
26	Memantamine	PLGA	Nanoprecipiation followed by ultrasonification	58.04nm	-23mV	89%	Higher concentration of drug at the target site	177
27	Donepezil and Memantine	_	Nano colloidal carrier prepared using low emulsion technique	16nm	-7.22mv	_	The concentration in the brain is much higher than free drug	178
28	Erythropoietin	Polysorbate80	SLN	219.9±15.6nm	_	41.4±3.6	The results showed SLNs potential ability to hinder Aβ effects	179
29	Leuprolide acetate	Chitosan	Nanoparticles	254.3±10.7	18.0±0.2mv	85.6±0.8	Great promise for AD was discovered for the chitosan nanoparticulate formulation of leuprolide acetate.	180
30	Escitalopram and Paroxetine	Lauroglycol 90 and PrecirolATO 5	Nano emulsion prepared using High-pressurehomogenization	165±2.01nm	11.2±0.400	44.5±5.23 and 83.1 ±8.49	Higher concentration of drug in the brain and lesser toxicity	181
31	Risperidone	Compritol888ATO	SLNs prepared by solvent diffusion-solvent evaportaion	148.05±0.85	-25.35±0.45	59.65±1.18%	Higher concentration of drug achieved by using nano formulation as compared to free drug	182
32	Zolmitriptan	Triglyceride	Micro emulsion prepared using titration	35±25nm	-38.90±2.05	98.77±0.83%	Effective delivery of drug to the brain	183
33	Amiloride	Carbitol	Nanoemulsion	89.36±11.18nm	-9.83±0.12mV	80.36%	Rapid onset of action due to direct nose-to-brain access	184
34	Rivastigmine	CPP peptide	Liposomes	166.3±17.4	-10.5±2.4	33.4±6.6	Improved brain delivery and BBB penetration.	185
35	Ziprasidone	Gelucire43/01 and 44/14	NLC was prepared using hot homogenization followed by ultra-sonification	119.62	_	70.83%	Higher concentration of drug in the brain as compared to free drug	186
36	Letrozole	Triacetin, tween 80, and PEG-400	Nano emulsion by aqueous titration method	95.59±2.34nm	-7.12±0.12mv	97.37±1.13%	Improved anticonvulsant activity	187
37	Piperine	Chitosan	Nanoparticles by dispersion	248.50nm	+56.30mv	81.70%	Increased bioavailability of drug	188
38	Erythropoietin	Polysorbate 80	SLNs using double emulsion method	219.9±15.6nm	-22.4±0.8mV	41.4±3.6	Enhanced neuroprotection	189
39	Queritin	PEG 660-stearate	Nanoemulsion using high pressure homozenization	131.00±0.25	+7.9±0.24	>99	Enhanced concentration of drug at the target site	190
40	Insulin	Poly(N-vinyl pyrrolidone)-co-acrylic acid nanogels	Nanogels	75	-12±6.9	74.03%	Changes in mucosal integrity were observed.	191
41	Temozolomide	Cyclodextrin conjugared Chitosan and PEG-adamantane polymer	Gold-nanoparticles by nucleophilic substitution	31.3±20nm	-15mV	82.89±8.14%	Intramuscular administration of temozolomide gold nanoparticles was performed. The results showed that the rat brain had a higher drug content.	192
42	Carbamazepine	Carboxymethyl chitosan	Nanoparticles	218.76±2.41	-33.3	80%	Greater drug concentration was found in several parts of the brain when carbamazepine-loaded dendrimers were used.	193
43	Haloperidol	Tween 20	Dendrimers	15.10±5.4	10.7±1.75	_	Haloperidol containing dendrimers were developed and administered through intranasal route. The study showed dendrimers can be a appropriate drug delivery system for drug targeting to brain for poorly water soluble drugs.	194
44	Bromocriptine	Chitosan	Polymeric nanoparticles were prepared using ionic gelation technique	161.3±4.7nm	+40.3±2.7mV	84.2±3.5	Enhanced concentration of drug.	195
45	Tarenflurbil	PLGA	Nanocarrier by emulsification and solvent diffusion method	<200nm	-23.13±2.32mV	64.11±2.21%	For intranasal delivery, tarenflubril was encased in PLGA nanoparticles. The efficiency of entrapment was enhanced. Evidence suggested that drug concentrations in the brain were higher.	196
46	Camptothecin	PEG, MPEG/ poly(ε-caprolactone)	Micelles	88.5±20.2	10.4±2.84	62.5±9.17	After the intratracheal injection of micelles loaded with camptothecin, rats with cerebral glioma tumours had an increase in survival time.	197
47	Doxorubicin	PLGA	Dendrimers	156±10.85nm	-10.0±2.1mV	19.01±1.58%	Higher permeability through BBB via intranasal administration	198
48	Disulfiram	PEG2000	Ion sensitive nanoemulsion	63.4±1.1nm	-23.5±0.2mV	89.02±0.32	The local nasal administration with minimal systemic distribution may explain why disulfiram-loaded intranasal nanoemulsion successfully inhibited tumour growth in vivo and prolonged the life span of glioma-bearing rats.	199
49	Nicardipine	Chitosan	Polymeric nanoparticles	439.6±11.9nm	+21.05±0.48mV	78	Intracerebral haemorrhage treatment options may include nicardipine-loaded nanoparticles, which have shown rapid drug transport to the brain after intranasal administration.	200
50	Rasagiline	Chitosan glutamate	Ionic gelation technology was used to prepare NPs	151.1±10.31	_	96.43±4.23	Enhanced bioavailability and brain uptake	201
51	Ropinirole	Chitosan	NPs prepared using ionic gelation technique	173.7±2.32		69.6±3.3	Increased concentration of drug at the target site	202
52	Venlafaxine	Hyaluronic acid	Transbilosomes were prepared using film hydration	185.6±4.9nm	-39.8±1.7mV	69.6±2.6nm	Higher bioavailability of VLF to the brain	203
53	Zonisamide	Carbopol	Microemulsion	_	_	54.95%	Enhanced bioavailability	204
54	Olanzapine	Chitosan	Ionotropic gelation	322±18	_	87.6±5.2	Improved systemic absorption	205

 

 

9. Conclusion and future prospect: 

Nanoparticulate delivery system is considered as a novel and promising route for a number of neurodegenerative diseases. Bypassing the blood-brain barrier (BBB), a major obstacle in neuropharmacology and by the intranasal route the medications can directly deliver to the brain. The use of nanoparticles enables targeted delivery to specific brain regions, decreased systemic adverse effects, and regulated and sustained release of therapeutic medicines. Previous research revealed that, a variety of therapeutic compounds, including as tiny molecules, peptides, proteins, and genes, can be delivered through intranasal administration. Due to the non-invasive nature of the administration method, intranasal nanoparticulate delivery systems have demonstrated potential in improving bioavailability, enhancing therapeutic efficacy, and improving patient compliance for neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been observed from past research that, Intranasal nanoparticulate delivery systems possess the capacity to lessen neuroinflammation, encourage neuroprotection, and support neuro-regeneration, thereby providing therapeutic advantages for delaying or stopping the progression of disease. Even though intranasal delivery has several benefits, there are still issues that must be pointed out and resolved. These include enhancing the stability and pharmacokinetics of the drug-loaded nanoparticles, establishment of safety, overcoming nasal mucosal clearance mechanisms and optimizing nanoparticle formulations for improved targeting and release features. Additional research is required to establish long-term impacts of intranasal delivery systems on the brain and general health. Combination medicines that target several pathogenic pathways of neurodegenerative illnesses may be delivered more easily via these platforms. Intranasal nanoparticlebased systems may be customized to meet the demands of particular patients as our knowledge of the genetic and molecular variances in neurodegenerative disorders expands, improving therapeutic results. Although pre-clinical research has yielded encouraging outcomes, clinical translation is essential to the broad use of intranasal nanoparticulate devices. Commercialising these treatments successfully will require overcoming regulatory obstacles, establishing safety and efficacy, and solving manufacturing scalability. Intranasal nanoparticulate delivery systems have a bright future ahead for the management of neurodegenerative illnesses. 

List of abbreviations:

BBB: Blood-Brain Barrier

CNS: Central Nervous System

CSF: Cerebro Spinal Fluid

EPR: Enhanced Permeability and Retention 

PEG: Polyethylene glycol 

SSRI: Serotonin specific reuptake inhibitor

NP: Nanoparticle

SLN: Solid Lipid Nanoparticle

Ethics approval and consent to participate: This manuscript is a review. Hence, no experiments in animals or humans are included in this study, so ethical approval and consent are not required.

Clinical Trial No: The manuscript is a review article (not a part of Clinical trial), hence no Clinical trial no is applicable.

Consent for publication: This manuscript does not contain any personal data. Hence, no consent is required/Not applicable

Availability of data and material: Data sharing does not apply to this article as no datasets were generated or analyzed during the current study. 

Conflict of interest: The authors declare no conflicts of interest.

Funding: The authors received no funding from private /Govt./other organisations to complete this manuscript.

Declaration of competing interest: The authors declare no conflict of interest. 

Acknowledgements: The authors are thankful to the Principal of Columbia Institute of Pharmacy, Raipur, Chhattisgarh, India and Dean, Pt J.N.M. Medical College, Raipur, Chhattisgarh, India for providing infrastructural and library facilities to complete this review.

 

References

[1] Park H, Otte A, Park K. Evolution of drug delivery systems: From 1950 to 2020 and beyond. J Control Release. 2022; 342:53-65. https://doi.org/10.1016/j.jconrel.2021.12.030 PMid:34971694 PMCid:PMC8840987

[2] Narine A, Mangal G. Conceptual study of Nasya Karma and its various applications. India: IAMJ; 2021.

[3] Boyetey MJ, Choi Y, Lee HY, Choi J. Nanotechnology-based delivery of therapeutics through the intranasal pathway and the blood-brain barrier for Alzheimer's disease treatment. Biomaterials Science. 2024;12(8):2007-18. https://doi.org/10.1039/D3BM02003G PMid:38456516

[4] Kim B, Park B, You S, et al. Cell membrane camouflaged nanoparticle strategy and its application in brain disease: a review. J Pharm Investing. 2024; 54:435-451. https://doi.org/10.1007/s40005-024-00680-z

[5] Wu D, Chen Q, Chen X, Han F, Chen Z, Wang Y. The blood-brain barrier: Structure, regulation and drug delivery. Signal Transduction and Targeted Therapy. 2023;8(1):217. https://doi.org/10.1038/s41392-023-01481-w PMid:37231000 PMCid:PMC10212980

[6] Simrah, Hafeez A, Usmani SA, Izhar MP. Transfersome, an ultra-deformable lipid-based drug nanocarrier: an updated review with therapeutic applications. Naunyn-Schmiedeberg's Arch Pharmacol. 2024 ;397(2):639-73. https://doi.org/10.1007/s00210-023-02670-8 PMid:37597094

[7] Qin L, Sun Y, Gao N, Ling G, Zhang P. Nanotechnology of inhalable vaccines for enhancing mucosal immunity. Drug Deliv Transl Res. 2024 ;14(3):597-620. https://doi.org/10.1007/s13346-023-01431-7 PMid:37747597

[8] Ezike TC, Okpala US, Onoja UL, Nwike CP, Ezeako EC, Okpara OJ, Okoroafor CC, Eze SC, Kalu OL, Odoh EC, Nwadike UG. Advances in drug delivery systems, challenges and future directions. Heliyon. 2023 ;9(6): e16732. https://doi.org/10.1016/j.heliyon.2023.e17488 PMid:37416680 PMCid:PMC10320272

[9] Feng X, Shi Y, Zhang Y, Lei F, Ren R, Tang X. Opportunities and challenges for inhalable nanomedicine formulations in respiratory diseases: a review. Int J Nanomedicine. 2024 ;19:1509-38. https://doi.org/10.2147/IJN.S446919 PMid:38384321 PMCid:PMC10880554

[10] Abdellatif AA, Mohammed HA, Khan RA, Singh V, Bouazzaoui A, Yusuf M, Akhtar N, Khan M, Al-Subaiyel A, Mohammed SA, Al-Omar MS. Nano-scale delivery: A comprehensive review of nano-structured devices, preparative techniques, site-specificity designs, biomedical applications, commercial products, and references to safety, cellular uptake, and organ toxicity. Nanotechnol Rev. 2021 ;10(1):1493-559. https://doi.org/10.1515/ntrev-2021-0096

[11] Koo J, Lim C, Oh KT. Recent advances in intranasal administration for brain-targeting delivery: a comprehensive review of lipid-based nanoparticles and stimuli-responsive gel formulations. Int J Nanomedicine. 2024; 19:1767-807. https://doi.org/10.2147/IJN.S439181 PMid:38414526 PMCid:PMC10898487

[12] Rabiee N, Ahmadi S, Afshari R, Khalaji S, Rabiee M, Bagherzadeh M, Fatahi Y, Dinarvand R, Tahriri M, Tayebi L, Hamblin MR. Polymeric nanoparticles for nasal drug delivery to the brain: relevance to Alzheimer's disease. Adv Ther. 2021;4(3):2000076. https://doi.org/10.1002/adtp.202000076

[13] Yan X, Sha X. Nanoparticle-mediated strategies for enhanced drug penetration and retention in the airway mucosa. Pharmaceutics. 2023; 15(10):2457. https://doi.org/10.3390/pharmaceutics15102457 PMid:37896217 PMCid:PMC10610050

[14] Huang D, Sun L, Huang L, Chen Y. Nanodrug delivery systems modulate tumor vessels to increase the enhanced permeability and retention effect. J Pers Med. 2021;11(2):124. https://doi.org/10.3390/jpm11020124 PMid:33672813 PMCid:PMC7917988

[15] Zi Y, Yang K, He J, Wu Z, Liu J, Zhang W. Strategies to enhance drug delivery to solid tumors by harnessing the EPR effects and alternative targeting mechanisms. Adv Drug Deliv Rev. 2022;188:114449. https://doi.org/10.1016/j.addr.2022.114449 PMid:35835353

[16] Niazi SK. Non-invasive drug delivery across the blood-brain barrier: a prospective analysis. Pharmaceutics. 2023;15(11):2599. https://doi.org/10.3390/pharmaceutics15112599 PMid:38004577 PMCid:PMC10674293

[17] de Barros C, Portugal I, Batain F, Portella D, Severino P, Cardoso J, Arcuri P, Chaud M, Alves T. Formulation, design and strategies for efficient nanotechnology-based nasal delivery systems. RPS Pharm Pharmacol Rep. 2022;1(1): rqac003. https://doi.org/10.1093/rpsppr/rqac003

[18] Spindler LM, Feuerhake A, Ladel S, Günday C, Flamm J, Günday-Türeli N, Türeli E, Tovar GE, Schindowski K, Gruber-Traub C. Nano-in-micro-particles consisting of PLGA nanoparticles embedded in chitosan microparticles via spray-drying enhances their uptake in the olfactory mucosa. Front Pharmacol. 2021; 12:732954. https://doi.org/10.3389/fphar.2021.732954 PMid:34539414 PMCid:PMC8440808

[19] Huang J, Dong G, Liang M, Wu X, Xian M, An Y, Zhan J, Xu L, Xu J, Sun W, Chen S. Toxicity of micro (nano) plastics with different size and surface charge on human nasal epithelial cells and rats via intranasal exposure. Chemosphere. 2022; 307:136093. https://doi.org/10.1016/j.chemosphere.2022.136093 PMid:36029863

[20] Gao X, Xiong Y, Chen H, Gao X, Dai J, Zhang Y, Zou W, Gao Y, Jiang Z, Han B. Mucus adhesion vs. mucus penetration? Screening nanomaterials for nasal inhalation by MD simulation. J Control Release. 2023; 353:366-79. https://doi.org/10.1016/j.jconrel.2022.11.051 PMid:36462640

[21] Guo Y, Ma Y, Chen X, Li M, Ma X, Cheng G, Xue C, Zuo YY, Sun B. Mucus penetration of surface-engineered nanoparticles in various pH microenvironments. ACS Nano. 2023;17(3):2813-28. https://doi.org/10.1021/acsnano.2c11147 PMid:36719858

[22] Mura P, Maestrelli F, Cirri M, Mennini N. Multiple roles of chitosan in mucosal drug delivery: an updated review. Mar Drugs. 2022;20(5):335. https://doi.org/10.3390/md20050335 PMid:35621986 PMCid:PMC9146108

[23] Bashiri G, Padilla MS, Swingle KL, Shepherd SJ, Mitchell MJ, Wang K. Nanoparticle protein corona: from structure and function to therapeutic targeting. Lab Chip. 2023;23(6):1432-66. https://doi.org/10.1039/D2LC00799A PMid:36655824 PMCid:PMC10013352

[24] Kulkarni R, Fanse S, Burgess DJ. Mucoadhesive drug delivery systems: a promising noninvasive approach to bioavailability enhancement. Part II: formulation considerations. Expert Opin Drug Deliv. 2023;20(3):413-34. https://doi.org/10.1080/17425247.2023.2181332 PMid:36803264

[25] Xu Y, Fourniols T, Labrak Y, Préat V, Beloqui A, des Rieux A. Surface modification of lipid-based nanoparticles. ACS Nano. 2022;16(5):7168-96. https://doi.org/10.1021/acsnano.2c02347 PMid:35446546

[26] Subramanian DA, Langer R, Traverso G. Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems. J Nanobiotechnology. 2022;20(1):362. https://doi.org/10.1186/s12951-022-01539-x PMid:35933341 PMCid:PMC9356434

[27] Mura P, Maestrelli F, Cirri M, Mennini N. Multiple roles of chitosan in mucosal drug delivery: an updated review. Mar Drugs. 2022;20(5):335. https://doi.org/10.3390/md20050335 PMid:35621986 PMCid:PMC9146108

[28] Hill DB, Button B, Rubinstein M, Boucher RC. Physiology and pathophysiology of human airway mucus. Physiol Rev. 2022; 102(4):1757-836. https://doi.org/10.1152/physrev.00004.2021 PMid:35001665 PMCid:PMC9665957

[29] Jia B, Zhang B, Li J, Qin J, Huang Y, Huang M, Ming Y, Jiang J, Chen R, Xiao Y, Du J. Emerging polymeric materials for treatment of oral diseases: design strategy towards a unique oral environment. Chem Soc Rev. 2024; 53(3):1120-55. https://doi.org/10.1039/D3CS01039B PMid:38507263

[30] Dhakar RC, Maurya SD, Tilak VK, Gupta AK, A review on factors affecting the design of nasal drug delivery system, International journal of drug delivery, 2011;3(2):194

[31] Prasher P, Sharma M, Singh SK, Gulati M, Jha NK, Gupta PK, Gupta G, Chellappan DK, Zacconi F, Pinto TD, Chan Y. Targeting mucus barrier in respiratory diseases by chemically modified advanced delivery systems. Chem Biol Interact. 2022;365:110048. https://doi.org/10.1016/j.cbi.2022.110048 PMid:35932910

[32] Croitoru GA, Pîrvulescu DC, Niculescu AG, Grumezescu AM, Antohi AM, Nicolae CL. Metallic nanomaterials-targeted drug delivery approaches for improved bioavailability, reduced side toxicity, and enhanced patient outcomes. Rom J Morphol Embryol. 2024;65(2):145. https://doi.org/10.47162/RJME.65.2.01 PMid:39020529 PMCid:PMC11384046

[33] Abla KK, Mehanna MM. Lipid-based nanocarriers challenging the ocular biological barriers: current paradigm and future perspectives. J Control Release. 2023;362:70-96. https://doi.org/10.1016/j.jconrel.2023.08.018 PMid:37591463

[34] Jawadi Z, Yang C, Haidar ZS, Santa Maria PL, Massa S. Bio-inspired muco-adhesive polymers for drug delivery applications. Polymers (Basel). 2022;14(24):5459. https://doi.org/10.3390/polym14245459 PMid:36559825 PMCid:PMC9785024

[35] Valibeknejad M, Abdoli SM, Alizadeh R, Mihăilă SM, Raoof A. Insights into transport in mucus barrier: exploring particle penetration through the intestinal mucus layer. J Drug Deliv Sci Technol. 2023;86:104752. https://doi.org/10.1016/j.jddst.2023.104752

[36] Xu C, Xu H, Zhu Z, Shi X, Xiao B. Recent advances in mucus-penetrating nanomedicines for oral treatment of colonic diseases. Expert Opin Drug Deliv. 2023;20(10):1371-85. https://doi.org/10.1080/17425247.2023.2242266 PMid:37498079

[37] Subramanian DA, Langer R, Traverso G. Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems. J Nanobiotechnology. 2022;20(1):362. https://doi.org/10.1186/s12951-022-01539-x PMid:35933341 PMCid:PMC9356434

[38] Chu JN, Traverso G. Foundations of gastrointestinal-based drug delivery and future developments. Nat Rev Gastroenterol Hepatol. 2022;19(4):219-38. https://doi.org/10.1038/s41575-021-00539-w PMid:34785786 PMCid:PMC12053541

[39] Feczko T. Polymeric nanotherapeutics acting at special regions of body. J Drug Deliv Sci Technol. 2021;64:102597. https://doi.org/10.1016/j.jddst.2021.102597

[40] Srujana S, Anjamma M, Alimuddin, Singh B, Dhakar RC, Natarajan S, Hechhu R. A Comprehensive Study on the Synthesis and Characterization of TiO2 Nanoparticles Using Aloe vera Plant Extract and Their Photocatalytic Activity against MB Dye. Adsorption Science & Technology. 2022;2022 https://doi.org/10.1155/2022/7244006

[41] Satapathy T, Panda PK. Solid lipid nanoparticles: a novel carrier in drug delivery system. Res J Pharm Dosage Forms Technol. 2013;5(2):56-61.

[42] Shi M, McHugh KJ. Strategies for overcoming protein and peptide instability in biodegradable drug delivery systems. Adv Drug Deliv Rev. 2023;199:114904. https://doi.org/10.1016/j.addr.2023.114904 PMid:37263542 PMCid:PMC10526705

[43] Prajapati SK, Maurya SD, Das MK, Tilak VK, Verma KK, Dhakar RC, Dendrimers in drug delivery, diagnosis and therapy: basics and potential applications, Journal of Drug Delivery and Therapeutics. 2016;6(1):67-92 https://doi.org/10.22270/jddt.v6i1.1190

[44] Ghosh M, Roy D, Thakur S, Singh A. Exploring the potential of nasal drug delivery for brain targeted therapy: a detailed analysis. Biopharm Drug Dispos. 2024;45(4-6):161-89. https://doi.org/10.1002/bdd.2400 PMid:39665188

[45] Zheng Y, Luo S, Xu M, He Q, Xie J, Wu J, Huang Y. Transepithelial transport of nanoparticles in oral drug delivery: from the perspective of surface and holistic property modulation. Acta Pharm Sin B. 2024;14(6):1234-52. https://doi.org/10.1016/j.apsb.2024.06.015 PMid:39309496 PMCid:PMC11413706

[46] Herdiana Y, Wathoni N, Shamsuddin S, Muchtaridi M. Drug release study of the chitosan-based nanoparticles. Heliyon. 2022;8(1):e08743. https://doi.org/10.1016/j.heliyon.2021.e08674 PMid:35028457 PMCid:PMC8741465

[47] Kesharwani D, Paul SD, Paliwal R, Satapathy T. Exploring potential of diacerin nanogel for topical application in arthritis: formulation development, QbD-based optimization and pre-clinical evaluation. Colloids Surf B Biointerfaces. 2023;223:113160. https://doi.org/10.1016/j.colsurfb.2023.113160 PMid:36736175

[48] Wu F, Qiu F, Wai-Keong SA, Diao Y. Smart dual-stimuli responsive nanoparticles for controlled anti-tumor drug release and cancer therapy. Anti-Cancer Agents Med Chem. 2021;21(10):1202-15. https://doi.org/10.2174/1871520620666200924110418 PMid:32972353

[49] Wang X, Zhong X, Li J, Liu Z, Cheng L. Inorganic nanomaterials with rapid clearance for biomedical applications. Chem Soc Rev. 2021;50(15):8669-742. https://doi.org/10.1039/D0CS00461H PMid:34156040

[50] Alagusundaram M, Jain NK, Begum MY, Parameswari SA, Nelson VK, Bayan MF, Chandrasekaran B. Development and characterization of gel-based buccoadhesive bilayer formulation of nifedipine. Gels. 2023;9(9):688. https://doi.org/10.3390/gels9090688 PMid:37754369 PMCid:PMC10530715

[51] Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem Rev. 2016;116(4):2602-63. https://doi.org/10.1021/acs.chemrev.5b00346 PMid:26854975 PMCid:PMC5509216

[52] Rivas CJ, Tarhini M, Badri W, Miladi K, Greige-Gerges H, Nazari QA, Rodríguez SA, Román RÁ, Fessi H, Elaissari A. Nanoprecipitation process: from encapsulation to drug delivery. Int J Pharm. 2017;532(1):66-81. https://doi.org/10.1016/j.ijpharm.2017.08.064 PMid:28801107

[53] Colinet I, Dulong V, Mocanu G, Picton L, Le Cerf D. Effect of chitosan coating on the swelling and controlled release of a poorly water-soluble drug from an amphiphilic and pH-sensitive hydrogel. Int J Biol Macromol. 2010;47(2):120-5. https://doi.org/10.1016/j.ijbiomac.2010.05.011 PMid:20471413

[54] Paul W, Sharma CP. Chitosan, a drug carrier for the 21st century: a review. STP Pharma Sci. 2000;10(1):5-22.

[55] Chen EY, Wang YC, Chen CS, Chin WC. Functionalized positive nanoparticles reduce mucin swelling and dispersion. PLoS One. 2010;5(11):e15434. https://doi.org/10.1371/journal.pone.0015434 PMid:21085670 PMCid:PMC2978103

[56] Varde NK, Pack DW. Microspheres for controlled release drug delivery. Expert Opin Biol Ther. 2004;4(1):35-51. https://doi.org/10.1517/14712598.4.1.35 PMid:14680467

[57] Engineer C, Parikh J, Raval A. Review on hydrolytic degradation behavior of biodegradable polymers from controlled drug delivery system. Trends Biomater Artif Organs. 2011;25(2):79-85.

[58] Djekic L. Novel mucoadhesive polymers for nasal drug delivery. In: Nasal Drug Delivery: Formulations, Developments, Challenges, and Solutions. 2023;189-234. https://doi.org/10.1007/978-3-031-23112-4_11 

[59] Anjali S, Abhijeet K, Ajay S, Kulkarni A. Nasal in situ gel: novel approach for nasal drug delivery. J Drug Deliv Ther. 2020;10(2):183-97. https://doi.org/10.22270/jddt.v10i2-s.4029

[60] Sahu M, Satapathy T, Bahadur S, Saha S, Purabiya P, Kaushik S, Netam AK, Prasad J. Preparation methods for nanoparticles: a smart carrier system for treatment of cancer. Int J Pharm Sci Rev Res. 2018;7(19):216-26.

[61] He S, Mu H. Microenvironmental pH modification in buccal/sublingual dosage forms for systemic drug delivery. Pharmaceutics. 2023;15(2):637. https://doi.org/10.3390/pharmaceutics15020637 PMid:36839959 PMCid:PMC9961113

[62] Shaibie NA, Ramli NA, Mohammad Faizal ND, Srichana T, Mohd Amin MC. Poly(N-isopropylacrylamide)-based polymers: recent overview for the development of temperature responsive drug delivery and biomedical applications. Macromol Chem Phys. 2023;224(20):2300157. https://doi.org/10.1002/macp.202300157

[63] Koo J, Lim C, Oh KT. Recent advances in intranasal administration for brain-targeting delivery: a comprehensive review of lipid-based nanoparticles and stimuli-responsive gel formulations. Int J Nanomedicine. 2024;19:1767-807. https://doi.org/10.2147/IJN.S439181 PMid:38414526 PMCid:PMC10898487

[64] Mohamed S, Nasr M, Salama A, Refai H. Novel lipid-polymer hybrid nanoparticles incorporated in thermosensitive in situ gel for intranasal delivery of terbutaline sulphate. J Microencapsul. 2020;37(8):577-94. https://doi.org/10.1080/02652048.2020.1826590 PMid:32969722

[65] Sunoqrot S, Hasan L, Alsadi A, Hamed R, Tarawneh O. Interactions of mussel-inspired polymeric nanoparticles with gastric mucin: implications for gastro-retentive drug delivery. Colloids Surf B Biointerfaces. 2017;156:1-8. https://doi.org/10.1016/j.colsurfb.2017.05.005 PMid:28499200

[66] Araújo F, Martins C, Azevedo C, Sarmento B. Chemical modification of drug molecules as strategy to reduce interactions with mucus. Adv Drug Deliv Rev. 2018;124:98-106. https://doi.org/10.1016/j.addr.2017.09.020 PMid:28964880

[67] Bandi SP, Kumbhar YS, Venuganti VV. Effect of particle size and surface charge of nanoparticles in penetration through intestinal mucus barrier. J Nanopart Res. 2020;22:1-11. https://doi.org/10.1007/s11051-020-04785-y

[68] Zeng L, An L, Wu X. Modeling drug-carrier interaction in the drug release from nanocarriers. J Drug Deliv. 2011;2011:370308. https://doi.org/10.1155/2011/370308 PMid:21845225 PMCid:PMC3154485

[69] Leal J, Smyth HD, Ghosh D. Physicochemical properties of mucus and their impact on transmucosal drug delivery. Int J Pharm. 2017;532(1):555-72. https://doi.org/10.1016/j.ijpharm.2017.09.018 PMid:28917986 PMCid:PMC5744044

]70] Pednekar DD, Liguori MA, Marques CN, Zhang T, Zhang N, Zhou Z, Amoako K, Gu H. From static to dynamic: a review on the role of mucus heterogeneity in particle and microbial transport. ACS Biomater Sci Eng. 2022;8(7):2825-48. https://doi.org/10.1021/acsbiomaterials.2c00182 PMid:35696291

[71] De La Rica R, Aili D, Stevens MM. Enzyme-responsive nanoparticles for drug release and diagnostics. Adv Drug Deliv Rev. 2012;64(11):967-78. https://doi.org/10.1016/j.addr.2012.01.002 PMid:22266127

[72] Araujo F, Martins C, Azevedo C, Sarmento B. Chemical modification of drug molecules as strategy to reduce interactions with mucus. Adv Drug Deliv Rev. 2018;124:98-106. https://doi.org/10.1016/j.addr.2017.09.020 PMid:28964880

[73] Ahmad R, Sardar M. Enzyme immobilization: an overview on nanoparticles as immobilization matrix. Biochem Anal Biochem. 2015;4(2):1.

[74] Sarkar MA. Drug metabolism in the nasal mucosa. Pharm Res. 1992; 9:1-9. https://doi.org/10.1023/A:1018911206646 PMid:1589391

[75] Uppal S, Italiya KS, Chitkara D, Mittal A. Nanoparticulate-based drug delivery systems for small molecule anti-diabetic drugs: An emerging paradigm for effective therapy. Acta Biomater. 2018;81:20-42. https://doi.org/10.1016/j.actbio.2018.09.049 PMid:30268916

[76] Kreuter J. Nanoparticulate systems for brain delivery of drugs. Adv Drug Deliv Rev. 2001;47(1):65-81. https://doi.org/10.1016/S0169-409X(00)00122-8 PMid:11251246

[77] Mu Q, Jiang G, Chen L, Zhou H, Fourches D, Tropsha A, et al. Chemical basis of interactions between engineered nanoparticles and biological systems. Chem Rev. 2014;114(15):7740-81. https://doi.org/10.1021/cr400295a PMid:24927254 PMCid:PMC4578874

[78] Srinivasarao M, Low PS. Ligand-targeted drug delivery. Chem Rev. 2017;117(19):12133-64. https://doi.org/10.1021/acs.chemrev.7b00013 PMid:28898067

[79] Frohlich E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomedicine. 2012;7:5577-91. https://doi.org/10.2147/IJN.S36111 PMid:23144561 PMCid:PMC3493258

[80] Forest V, Pourchez J. Preferential binding of positive nanoparticles on cell membranes is due to electrostatic interactions: A too simplistic explanation that does not take into account the nanoparticle protein corona. Mater Sci Eng C. 2017;70:889-96. https://doi.org/10.1016/j.msec.2016.09.016 PMid:27770966

[81] Salatin S, Maleki Dizaj S, Yari Khosroushahi A. Effect of the surface modification, size, and shape on cellular uptake of nanoparticles. Cell Biol Int. 2015;39(8):881-90. https://doi.org/10.1002/cbin.10459 PMid:25790433

[82] Yang Y, Nie D, Liu Y, Yu M, Gan Y. Advances in particle shape engineering for improved drug delivery. Drug Discov Today. 2019;24(2):575-83. https://doi.org/10.1016/j.drudis.2018.10.006 PMid:30342244

[83] Karimi M, Ghasemi A, Zangabad PS, Rahighi R, Basri SM, Mirshekari H, et al. Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chem Soc Rev. 2016;45(5):1457-501. https://doi.org/10.1039/C5CS00798D PMid:26776487 PMCid:PMC4775468

[84] Fang RH, Kroll AV, Gao W, Zhang L. Cell membrane coating nanotechnology. Adv Mater. 2018;30(23):1706759. https://doi.org/10.1002/adma.201706759 PMid:29582476 PMCid:PMC5984176

[85] Maghsoudnia N, Eftekhari RB, Sohi AN, Zamzami A, Dorkoosh FA. Application of nano-based systems for drug delivery and targeting: a review. J Nanopart Res. 2020;22:1-41. https://doi.org/10.1007/s11051-020-04959-8

[86] Gijs MA, Lacharme F, Lehmann U. Microfluidic applications of magnetic particles for biological analysis and catalysis. Chem Rev. 2010;110(3):1518-63. https://doi.org/10.1021/cr9001929 PMid:19961177

[87] Shen S, Wu Y, Liu Y, Wu D. High drug-loading nanomedicines: progress, current status, and prospects. Int J Nanomedicine. 2017;12:4085-109. https://doi.org/10.2147/IJN.S132780 PMid:28615938 PMCid:PMC5459982

[88] Sun J, Lu Y, He L, Pang J, Yang F, Liu Y. Colorimetric sensor array based on gold nanoparticles: Design principles and recent advances. TrAC Trends Anal Chem. 2020;122:115754. https://doi.org/10.1016/j.trac.2019.115754

[89] Stolarczyk JK, Deak A, Brougham DF. Nanoparticle clusters: assembly and control over internal order, current capabilities, and future potential. Adv Mater. 2016;28(27):5400-24. https://doi.org/10.1002/adma.201505350 PMid:27411644

[90] Shen S, Wu Y, Liu Y, Wu D. High drug-loading nanomedicines: progress, current status, and prospects. Int J Nanomedicine. 2017;12:4085-109. https://doi.org/10.2147/IJN.S132780 PMid:28615938 PMCid:PMC5459982

[91] Liu Y, Yang G, Jin S, Xu L, Zhao CX. Development of high‐drug‐loading nanoparticles. ChemPlusChem. 2020;85(9):2143-57. https://doi.org/10.1002/cplu.202000496 PMid:32864902

[92] Wu D, Chen Q, Chen X, Han F, Chen Z, Wang Y. The blood-brain barrier: structure, regulation and drug delivery. Signal Transduct Target Ther. 2023;8(1):217. https://doi.org/10.1038/s41392-023-01481-w PMid:37231000 PMCid:PMC10212980

[93] Correia AC, Monteiro AR, Silva R, Moreira JN, Lobo JS, Silva AC. Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood-brain barrier to manage neurological disorders. Adv Drug Deliv Rev. 2022;189:114485. https://doi.org/10.1016/j.addr.2022.114485 PMid:35970274

[94] D'souza AA, Shegokar R. Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications. Expert Opin Drug Deliv. 2016;13(9):1257-75. https://doi.org/10.1080/17425247.2016.1182485 PMid:27116988

[95] Pasarin D, Ghizdareanu AI, Enascuta CE, Matei CB, Bilbie C, Paraschiv-Palada L, et al. Coating materials to increase the stability of liposomes. Polymers. 2023;15(3):782. https://doi.org/10.3390/polym15030782 PMid:36772080 PMCid:PMC10004256

[96] Cunha S, Amaral MH, Lobo JS, Silva A. Lipid nanoparticles for nasal/intranasal drug delivery. Crit Rev Ther Drug Carrier Syst. 2017;34(3). https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2017018693 PMid:28845761

[97] Pahor DA. The human nose & smell. Theology Med Unique Des Hum Body. 2023;21.

[98] Meng X, Zhu G. Nasal septal swell body: a distinctive structure in the nasal cavity. Ear Nose Throat J. 2021;100(8):NP362-9. https://doi.org/10.1177/01455613211010093 PMid:33881954

[99] Haghnegahdar A, Bharadwaj R, Feng Y. Exploring the role of nasal hair in inhaled airflow and coarse dust particle dynamics in a nasal cavity: A CFD-DEM study. Powder Technol. 2023;427:118710. https://doi.org/10.1016/j.powtec.2023.118710

[100] Beachey W. Respiratory Care Anatomy and Physiology: Foundations for Clinical Practice. Elsevier Health Sciences; 2022.

[101] Shang Y, Inthavong K, Qiu D, Singh N, He F, Tu J. Prediction of nasal spray drug absorption influenced by mucociliary clearance. PLoS One. 2021;16(1):e0246007. https://doi.org/10.1371/journal.pone.0246007 PMid:33507973 PMCid:PMC7842989

[102] Roe K. The epithelial cell types and their multi-phased defenses against fungi and other pathogens. Clin Chim Acta. 2024;119889. https://doi.org/10.1016/j.cca.2024.119889 PMid:39117034

[103] Azman M, Sabri AH, Anjani QK, Mustaffa MF, Hamid KA. Intestinal absorption study: challenges and absorption enhancement strategies in improving oral drug delivery. Pharmaceuticals. 2022;15(8):975. https://doi.org/10.3390/ph15080975 PMid:36015123 PMCid:PMC9412385

[104] Khunt D, Misra M. An overview of anatomical and physiological aspects of the nose and the brain. In: Direct Nose-to-Brain Drug Delivery. 2021; p. 3-14. https://doi.org/10.1016/B978-0-12-822522-6.00029-1

[105] Terrier LM, Hadjikhani N, Destrieux C. The trigeminal pathways. J Neurol. 2022;269(7):3443-60. https://doi.org/10.1007/s00415-022-11002-4 PMid:35249132

[106] Crowe TP, Hsu WH. Evaluation of recent intranasal drug delivery systems to the central nervous system. Pharmaceutics. 2022;14(3):629. https://doi.org/10.3390/pharmaceutics14030629 PMid:35336004 PMCid:PMC8950509

[107] Zhang R, Zhang L, Li P, Pang K, Liu H, Tian L. Epithelial barrier in the nasal mucosa, related risk factors and diseases. Int Arch Allergy Immunol. 2023;184(5):481-501. https://doi.org/10.1159/000528969 PMid:36724763 PMCid:PMC10137320

[108] Adivitiya, Kaushik MS, Chakraborty S, Veleri S, Kateriya S. Mucociliary respiratory epithelium integrity in molecular defense and susceptibility to pulmonary viral infections. Biology. 2021;10(2):95. https://doi.org/10.3390/biology10020095 PMid:33572760 PMCid:PMC7911113

[109] Yan X, Sha X. Nanoparticle-mediated strategies for enhanced drug penetration and retention in the airway mucosa. Pharmaceutics. 2023;15(10):2457. https://doi.org/10.3390/pharmaceutics15102457 PMid:37896217 PMCid:PMC10610050

[110] Rabiee N, Ahmadi S, Afshari R, Khalaji S, Rabiee M, Bagherzadeh M, et al. Polymeric nanoparticles for nasal drug delivery to the brain: relevance to Alzheimer's disease. Adv Ther. 2021;4(3):2000076. https://doi.org/10.1002/adtp.202000076

[111] Montegiove N, Calzoni E, Emiliani C, Cesaretti A. Biopolymer nanoparticles for nose-to-brain drug delivery: a new promising approach for the treatment of neurological diseases. J Funct Biomater. 2022;13(3):125. https://doi.org/10.3390/jfb13030125 PMid:36135560 PMCid:PMC9504125

[112] Gandhi S, Shastri DH, Shah J, Nair AB, Jacob S. Nasal delivery to the brain: harnessing nanoparticles for effective drug transport. Pharmaceutics. 2024;16(4):481. https://doi.org/10.3390/pharmaceutics16040481 PMid:38675142 PMCid:PMC11055100

[113] Praganta J. Clinical Effects of Advanced Platelet-Rich Fibrin (A-PRF) on the Outcomes of Third Molar Removal Surgery [Doctoral dissertation]. University of Otago; 2021.

[114] Arslan D, Unal Cevik I. Interactions between the painful disorders and the autonomic nervous system. Agri J Turk Soc Algol. 2022;34(3). https://doi.org/10.14744/agri.2021.43078 PMid:35792695

[115] Luciani-Giacobbe LC, Sanchez MF, Olivera ME. Nasal route of drug delivery. In: The ADME Encyclopedia: A Comprehensive Guide on Biopharmacy and Pharmacokinetics. Cham: Springer; 2022. p. 660-70. https://doi.org/10.1007/978-3-030-84860-6_102

[116] Khunt D, Misra M. An overview of anatomical and physiological aspects of the nose and the brain. In: Direct Nose-to-Brain Drug Delivery. 2021; p. 3-14. https://doi.org/10.1016/B978-0-12-822522-6.00029-1

[117] Yokel RA. Direct nose to the brain nanomedicine delivery presents a formidable challenge. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022;14(2):e1767. https://doi.org/10.1002/wnan.1767 PMid:34957707

[118] Fritzsch B, Elliott KL, Yamoah EN. Neurosensory development of the four brainstem-projecting sensory systems and their integration in the telencephalon. Front Neural Circuits. 2022;16:913480. https://doi.org/10.3389/fncir.2022.913480 PMid:36213204 PMCid:PMC9539932

[119] Yeomans DC, Hanson LR, Carson DS, Tunstall BJ, Lee MR, Tzabazis AZ, et al. Nasal oxytocin for the treatment of psychiatric disorders and pain: achieving meaningful brain concentrations. Transl Psychiatry. 2021;11(1):388. https://doi.org/10.1038/s41398-021-01511-7 PMid:34247185 PMCid:PMC8272715

[120] Lee D, Minko T. Nanotherapeutics for nose-to-brain drug delivery: an approach to bypass the blood-brain barrier. Pharmaceutics. 2021;13(12):2049. https://doi.org/10.3390/pharmaceutics13122049 PMid:34959331 PMCid:PMC8704573

[121] Park KS. Nervous system. In: Humans and Electricity: Understanding Body Electricity and Applications. Cham: Springer; 2023. p. 27-51. https://doi.org/10.1007/978-3-031-20784-6_2

[122] Mohapatra P, Gopikrishnan M, Doss CGP, Chandrasekaran N. How precise are nanomedicines in overcoming the blood-brain barrier? A comprehensive review of the literature. Int J Nanomedicine. 2024;19:2441-67. https://doi.org/10.2147/IJN.S442520 PMid:38482521 PMCid:PMC10932758

[123] Moradi F, Dashti N. Targeting neuroinflammation by intranasal delivery of nanoparticles in neurological diseases: a comprehensive review. Naunyn Schmiedebergs Arch Pharmacol. 2022;395(2):133-48 https://doi.org/10.1007/s00210-021-02196-x   PMid:34982185

[124] Campora S, Ghersi G. Recent developments and applications of smart nanoparticles in biomedicine. Nanotechnol Rev. 2022;11(1):2595-631. https://doi.org/10.1515/ntrev-2022-0148

[125] Correia AC, Monteiro AR, Silva R, Moreira JN, Lobo JS, Silva AC. Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: crossing or circumventing the blood-brain barrier to manage neurological disorders. Adv Drug Deliv Rev. 2022;189:114485 https://doi.org/10.1016/j.addr.2022.114485  PMid:35970274

[126] Zhang R, Zhang L, Li P, Pang K, Liu H, Tian L. Epithelial barrier in the nasal mucosa, related risk factors and diseases. Int Arch Allergy Immunol. 2023;184(5):481-501 https://doi.org/10.1159/000528969 PMid:36724763 PMCid:PMC10137320

[127] Rabiee N, Ahmadi S, Afshari R, Khalaji S, Rabiee M, Bagherzadeh M, et al. Polymeric nanoparticles for nasal drug delivery to the brain: relevance to Alzheimer's disease. Adv Ther. 2021;4(3):2000076. https://doi.org/10.1002/adtp.202000076

[128] Khunt D, Misra M. An overview of anatomical and physiological aspects of the nose and the brain. In: Direct Nose-to-Brain Drug Delivery. 2021; p. 3-14. https://doi.org/10.1016/B978-0-12-822522-6.00029-1

[129] Akram J, Akbar NS. Electroosmotically actuated peristaltic-ciliary flow of propylene glycol + water conveying titania nanoparticles. Sci Rep. 2023;13(1):11801. https://doi.org/10.1038/s41598-023-38820-4 PMid:37479868 PMCid:PMC10362056

[130] Moreno-Mendieta S, Guillén D, Vasquez-Martínez N, Hernández-Pando R, Sánchez S, Rodríguez-Sanoja R. Understanding the phagocytosis of particles: the key for rational design of vaccines and therapeutics. Pharm Res. 2022;39(8):1823-49. https://doi.org/10.1007/s11095-022-03301-2 PMid:35739369

[131] Moradi F, Dashti N. Targeting neuroinflammation by intranasal delivery of nanoparticles in neurological diseases: A comprehensive review. Naunyn-Schmiedeberg's Archives of Pharmacology. 2022 ;395(2):133-48. https://doi.org/10.1007/s00210-021-02196-x PMid:34982185

[132] Montegiove N, Calzoni E, Emiliani C, Cesaretti A. Biopolymer nanoparticles for nose-to-brain drug delivery: a new promising approach for the treatment of neurological diseases. J Funct Biomater. 2022;13(3):125. https://doi.org/10.3390/jfb13030125 PMid:36135560 PMCid:PMC9504125

[133] Pho T, Champion JA. Surface engineering of protein nanoparticles modulates transport, adsorption, and uptake in mucus. ACS Appl Mater Interfaces. 2022;14(46):51697-710. https://doi.org/10.1021/acsami.2c14670 PMid:36354361

[134] Guo C, Yuan H, Wang Y, Feng Y, Zhang Y, Yin T, et al. The interplay between PEGylated nanoparticles and blood immune system. Adv Drug Deliv Rev. 2023;200:115044. https://doi.org/10.1016/j.addr.2023.115044 PMid:37541623

[135] Nejati K, Dadashpour M, Gharibi T, Mellatyar H, Akbarzadeh A. Biomedical applications of functionalized gold nanoparticles: a review. J Clust Sci. 2021;32(1):1-6. https://doi.org/10.1007/s10876-020-01955-9

[136] Shi L, Zhang J, Zhao M, Tang S, Cheng X, Zhang W, et al. Effects of polyethylene glycol on the surface of nanoparticles for targeted drug delivery. Nanoscale. 2021;13(24):10748-64. https://doi.org/10.1039/D1NR02065J PMid:34132312

[137] Niculescu AG, Bîrcă AC, Grumezescu AM. New applications of lipid and polymer-based nanoparticles for nucleic acids delivery. Pharmaceutics. 2021;13(12):2053. https://doi.org/10.3390/pharmaceutics13122053 PMid:34959335 PMCid:PMC8708541

[138] Haripriyaa M, Suthindhiran K. Pharmacokinetics of nanoparticles: current knowledge, future directions and its implications in drug delivery. Future J Pharm Sci. 2023;9(1):113. https://doi.org/10.1186/s43094-023-00569-y

[139] Awashra M, Młynarz P. The toxicity of nanoparticles and their interaction with cells: an in vitro metabolomic perspective. Nanoscale Adv. 2023;5(10):2674-723. https://doi.org/10.1039/D2NA00534D PMid:37205285 PMCid:PMC10186990

[140] Aswathi VP, Meera S, Maria CA, Nidhin M. Green synthesis of nanoparticles from biodegradable waste extracts and their applications: a critical review. Nanotechnol Environ Eng. 2023;8(2):377-97. https://doi.org/10.1007/s41204-022-00276-8 PMCid:PMC9399584

[141] Huang Y, Wang J, Jiang K, Chung EJ. Improving kidney targeting: the influence of nanoparticle physicochemical properties on kidney interactions. J Control Release. 2021;334:127-37. https://doi.org/10.1016/j.jconrel.2021.04.016 PMid:33892054 PMCid:PMC8192458

[142] Xu M, Qi Y, Liu G, Song Y, Jiang X, Du B. Size-dependent in vivo transport of nanoparticles: implications for delivery, targeting, and clearance. ACS Nano. 2023;17(21):20825-49. https://doi.org/10.1021/acsnano.3c05853 PMid:37921488

[143] Vitulo M, Gnodi E, Meneveri R, Barisani D. Interactions between nanoparticles and intestine. Int J Mol Sci. 2022;23(8):4339. https://doi.org/10.3390/ijms23084339 PMid:35457155 PMCid:PMC9024817

[144] Crowe TP, Hsu WH. Evaluation of recent intranasal drug delivery systems to the central nervous system. Pharmaceutics. 2022;14(3):629. https://doi.org/10.3390/pharmaceutics14030629 PMid:35336004 PMCid:PMC8950509

[145] Bharadwaj VN, Tzabazis AZ, Klukinov M, Manering NA, Yeomans DC. Intranasal administration for pain: oxytocin and other polypeptides. Pharmaceutics. 2021;13(7):1088. https://doi.org/10.3390/pharmaceutics13071088 PMid:34371778 PMCid:PMC8309171

[146] Egbuna C, Rudrapal M, editors. Phytochemical Drug Discovery for Central Nervous System Disorders: Biochemistry and Therapeutic Effects. John Wiley & Sons; 2023. https://doi.org/10.1002/9781119794127

[147] Maher R, Moreno-Borrallo A, Jindal D, Mai BT, Ruiz-Hernandez E, Harkin A. Intranasal polymeric and lipid-based nanocarriers for CNS drug delivery. Pharmaceutics. 2023;15(3):746. https://doi.org/10.3390/pharmaceutics15030746 PMid:36986607 PMCid:PMC10051709

[148] Liu J, Cabral H, Mi P. Nanocarriers address intracellular barriers for efficient drug delivery, overcoming drug resistance, subcellular targeting and controlled release. Adv Drug Deliv Rev. 2024;115239. https://doi.org/10.1016/j.addr.2024.115239 PMid:38437916

[149] Dighe S, Jog S, Momin M, Sawarkar S, Omri A. Intranasal drug delivery by nanotechnology: advances in and challenges for Alzheimer's disease management. Pharmaceutics. 2023;16(1):58. https://doi.org/10.3390/pharmaceutics16010058 PMid:38258068 PMCid:PMC10820353

[150] Lamptey RN, Chaulagain B, Trivedi R, Gothwal A, Layek B, Singh J. A review of the common neurodegenerative disorders: current therapeutic approaches and the potential role of nanotherapeutics. Int J Mol Sci. 2022;23(3):1851. https://doi.org/10.3390/ijms23031851 PMid:35163773 PMCid:PMC8837071

[151] Wang X, Chi N, Tang X. Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting. Eur J Pharm Biopharm. 2008;70:735-40. https://doi.org/10.1016/j.ejpb.2008.07.005 PMid:18684400

[152] Wilson B, Samanta MK, Muthu MS, Vinothapooshan G. Design and evaluation of chitosan nanoparticles as novel drug carrier for the delivery of rivastigmine to treat Alzheimer's disease. Ther Deliv. 2011;2:599-609. https://doi.org/10.4155/tde.11.21 PMid:22833977

[153] Fazil M, Md S, Haque S, Kumar M, Baboota S, Sahni JK, Ali J. Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting. Eur J Pharm Sci. 2012;47(1):6-15. https://doi.org/10.1016/j.ejps.2012.04.013 PMid:22561106

[154] Bhavna B, Shadab A, Baboota S, Sahni JK, Bhatnagar A, Ali J. Preparation, characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting. Drug Dev Ind Pharm. 2014;40:278-87. https://doi.org/10.3109/03639045.2012.758130 PMid:23369094

[155] Satapathy T, Panda PK, Mishra G. Comparative evaluation of in vitro antioxidant, amylase inhibition and cytotoxic activity of Cur-Pip dual drug loaded nanoparticles. In: Advances in Biomedical Engineering and Technology: Select Proceedings of ICBEST 2018. Singapore: Springer; 2020. p. 129-39. https://doi.org/10.1007/978-981-15-6329-4_12

[156] Andrade S, Pereira MC, Loureiro JA. Caffeic acid loaded into engineered lipid nanoparticles for Alzheimer's disease therapy. Colloids Surf B Biointerfaces. 2023;225:113270. https://doi.org/10.1016/j.colsurfb.2023.113270 PMid:36996633

[157] Yin Z, Zhang Z, Gao D, Luo G, Ma T, Wang Y, et al. Stepwise coordination-driven metal-phenolic nanoparticle as a neuroprotection enhancer for Alzheimer's disease therapy. ACS Appl Mater Interfaces. 2023;15(1):524-40. https://doi.org/10.1021/acsami.2c18060 PMid:36542560

[158] Georgieva D, Nikolova D, Vassileva E, Kostova B. Chitosan-based nanoparticles for targeted nasal galantamine delivery as a promising tool in Alzheimer's disease therapy. Pharmaceutics. 2023;15(3):829. https://doi.org/10.3390/pharmaceutics15030829 PMid:36986689 PMCid:PMC10056147

[159] Luppi B, Bigucci F, Corace G, Delucca A, Cerchiara T, Sorrenti M, et al. Albumin nanoparticles carrying cyclodextrins for nasal delivery of the anti-Alzheimer drug tacrine. Eur J Pharm Sci. 2011;44(4):559-65. https://doi.org/10.1016/j.ejps.2011.10.002 PMid:22009109

[160] Zara GP, Cavalli R, Bargoni A, Fundarò A, Vighetto D, Gasco MR. Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues. J Drug Target. 2002;10(4):327-35. https://doi.org/10.1080/10611860290031868 PMid:12164381

[161] Yan D, Qu X, Chen M, Wang J, Li X, Zhang Z, et al. Functionalized curcumin/ginsenoside Rb1 dual-loaded liposomes: targeting the blood-brain barrier and improving pathological features associated in APP/PS-1 mice. J Drug Deliv Sci Technol. 2023;86:104633. https://doi.org/10.1016/j.jddst.2023.104633

[162] Mittal G, Sahana DK, Bhardwaj V, Ravi Kumar MN. Estradiol loaded PLGA nanoparticles for oral administration: effect of polymer molecular weight and copolymer composition on release behavior in vitro and in vivo. J Control Release. 2007;119(1):77-85. https://doi.org/10.1016/j.jconrel.2007.01.016 PMid:17349712

[163] Salatin S, Barar J, Barzegar-Jalali M, Adibkia K, Kiafar F, Jelvehgari M. Development of a nanoprecipitation method for the entrapment of a very water-soluble drug into Eudragit RL nanoparticles. Res Pharm Sci. 2017;12(1):1-14. https://doi.org/10.4103/1735-5362.199041 PMid:28255308 PMCid:PMC5333474

[164] Gao X, Wu B, Zhang Q, Chen J, Zhu J, Zhang W, et al. Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration. J Control Release. 2007;121(3):156-67. https://doi.org/10.1016/j.jconrel.2007.05.026 PMid:17628165

[165] Bari NK, Fazil M, Hassan MQ, Haider MR, Gaba B, Narang JK, et al. Brain delivery of buspirone hydrochloride chitosan nanoparticles for the treatment of general anxiety disorder. Int J Biol Macromol. 2015;81:49-59. https://doi.org/10.1016/j.ijbiomac.2015.07.041 PMid:26210037

[166] Fatouh AM, Elshafeey AH, Abdelbary A. Intranasal agomelatine solid lipid nanoparticles to enhance brain delivery: formulation, optimization and in vivo pharmacokinetics. Drug Des Dev Ther. 2017;11:1815-25. https://doi.org/10.2147/DDDT.S102500 PMid:28684900 PMCid:PMC5484509

[167] Elsenosy FM, Abdelbary GA, Elshafeey AH, Elsayed I, Fares AR. Brain targeting of duloxetine HCl via intranasal delivery of loaded cubosomal gel: in vitro characterization, ex vivo permeation, and in vivo biodistribution studies. Int J Nanomedicine. 2020;15:9517-37. https://doi.org/10.2147/IJN.S277352 PMid:33324051 PMCid:PMC7732760

[168] Ravouru N, Kondreddy P, Korakanchi D. Formulation and evaluation of niosomal nasal drug delivery system of folic acid for brain targeting. Curr Drug Discov Technol. 2013;10(4):270-82. https://doi.org/10.2174/15701638113109990031 PMid:23863098

[169] Singh D, Rashid M, Hallan SS, Mehra NK, Prakash A, Mishra N. Pharmacological evaluation of nasal delivery of selegiline hydrochloride-loaded thiolated chitosan nanoparticles for the treatment of depression. Artif Cells Nanomed Biotechnol. 2016;44(3):865-77.

[170] Haque S, Md S, Sahni JK, Ali J, Baboota S. Development and evaluation of brain targeted intranasal alginate nanoparticles for treatment of depression. J Psychiatr Res. 2014;48(1):1-12. https://doi.org/10.1016/j.jpsychires.2013.10.011 PMid:24231512

[171] Taymouri S, Shahnamnia S, Mesripour A, Varshosaz J. In vitro and in vivo evaluation of an ionic sensitive in situ gel containing nanotransfersomes for aripiprazole nasal delivery. Pharm Dev Technol. 2021;26(8):867-79. https://doi.org/10.1080/10837450.2021.1948571 PMid:34193009

[172] Yasir M, Sara UVS. Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation. Acta Pharm Sin B. 2014;4(6):454-63. https://doi.org/10.1016/j.apsb.2014.10.005 PMid:26579417 PMCid:PMC4629108

[173] Patel MR, Patel RB, Thakore SD, Solanki AB. Brain targeted delivery of lurasidone HCl via nasal administration of mucoadhesive nanoemulsion formulation for the potential management of schizophrenia. Pharm Dev Technol. 2020;25(8):1018-30. https://doi.org/10.1080/10837450.2020.1772292 PMid:32432956

[174] Meng Q, Wang A, Hua H, Jiang Y, Wang Y, Mu H, et al. Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer's disease. Int J Nanomedicine. 2018;13:705-18. https://doi.org/10.2147/IJN.S151474 PMid:29440896 PMCid:PMC5798568

[175] Ahmad N, Ahmad R, Naqvi AA, Alam MA, Samim M, Iqbal Z, et al. Quantification of rutin in rat brain by UHPLC/ESI-Q-TOF-MS/MS after intranasal administration of rutin loaded chitosan nanoparticles. EXCLI J. 2016;15:518-31.

[176] Kaur A, Nigam K, Tyagi A, et al. A preliminary pharmacodynamic study for the management of Alzheimer's disease using memantine-loaded PLGA nanoparticles. AAPS PharmSciTech. 2022;23:298. https://doi.org/10.1208/s12249-022-02449-9 PMid:36380129

[177] Handa M, Sanap SN, Bhatta RS, Patil GP, Palkhade R, Singh DP, et al. Simultaneous intranasal codelivery of donepezil and memantine in a nanocolloidal carrier: optimization, pharmacokinetics, and pharmacodynamics studies. Mol Pharm. 2023;20(9):4714-28. https://doi.org/10.1021/acs.molpharmaceut.3c00454 PMid:37523676

[178] Tao Y, Li C, Yao A, Qu Y, Qin L, Xiong Z, et al. Intranasal administration of erythropoietin rescues the photoreceptors in degenerative retina: a noninvasive method to deliver drugs to the eye. Drug Deliv. 2019;26(1):78-88. https://doi.org/10.1080/10717544.2018.1556361 PMid:30744451 PMCid:PMC6374977

[179] Pandya T, Dharamsi A. Intranasal delivery of leuprolide acetate chitosan nanoparticles for treatment of Alzheimer's disease. Drug Deliv Lett. 2023;13(2):120-32. https://doi.org/10.2174/2210303113666230120124831

[180] Silva S, Bicker J, Fonseca C, Ferreira NR, Vitorino C, Alves G, et al. Encapsulated escitalopram and paroxetine intranasal co-administration: in vitro/in vivo evaluation. Front Pharmacol. 2021;12:751321. https://doi.org/10.3389/fphar.2021.751321 PMid:34925013

[181] Patel S, Chavhan S, Soni H, Babbar AK, Mathur R, Mishra AK, et al. Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route. J Drug Target. 2010;19(6):468-74. https://doi.org/10.3109/1061186X.2010.523787 PMid:20958095

[182] Vyas TK, Babbar AK, Sharma RK, Misra A. Intranasal mucoadhesive microemulsions of zolmitriptan: preliminary studies on brain-targeting. J Drug Target. 2005;13(5):317-24. https://doi.org/10.1080/10611860500246217 PMid:16199375

[183] Yellepeddi V, Sayre C, Burrows A, Watt K, Davies S, Strauss J, Battaglia M. Stability of extemporaneously compounded amiloride nasal spray. PLoS One. 2020;15(7):e0232435. https://doi.org/10.1371/journal.pone.0232435 PMid:32649677 PMCid:PMC7351165

[184] Yang ZZ, Zhang YQ, Wang ZZ, Wu K, Lou JN, Qi XR. Enhanced brain distribution and pharmacodynamics of rivastigmine by liposomes following intranasal administration. Int J Pharm. 2013;452(1-2):344-54. https://doi.org/10.1016/j.ijpharm.2013.05.009 PMid:23680731

[185] Sivadasu P, Gowda DV, Siddaramaiah H, Hemalatha S. Ziprasidone hydrochloride loaded nanostructured lipid carriers for intranasal delivery: optimization and in vivo studies. Int J Appl Pharm. 2020;12(1):31-41. https://doi.org/10.22159/ijap.2020v12i1.35683

[186] Iqbal R, Ahmed S, Jain GK, Vohora D. Design and development of letrozole nanoemulsion: a comparative evaluation of brain targeted nanoemulsion with free letrozole against status epilepticus and neurodegeneration in mice. Int J Pharm. 2019;565:20-32. https://doi.org/10.1016/j.ijpharm.2019.04.076 PMid:31051232

[187] Elnaggar YSR, Etman SM, Abdelmonsif DA, Abdallah OY. Intranasal piperine-loaded chitosan nanoparticles as brain-targeted therapy in Alzheimer's disease: optimization, biological efficacy, and potential toxicity. J Pharm Sci. 2015;104(10):3544-56. https://doi.org/10.1002/jps.24557

[188] Maurice T, Mustafa MH, Desrumaux C, et al. Intranasal formulation of erythropoietin showed potent protective activity against amyloid toxicity in the Aβ25-35 non-transgenic mouse model of Alzheimer's disease. J Psychopharmacol. 2013;27(11):1044-57. https://doi.org/10.1177/0269881113494939 Mid:23813967

[189] Vaz G, Clementino A, Mitsou E, Ferrari E, Buttini F, Sissa C, et al. In vitro evaluation of curcumin- and quercetin-loaded nanoemulsions for intranasal administration: effect of surface charge and viscosity. Pharmaceutics. 2022;14:194. https://doi.org/10.3390/pharmaceutics14010194 PMid:35057089 PMCid:PMC8779979

[190] Picone P, Sabatino MA, Ditta LA, Amato A, San Biagio PL, Mulè F, et al. Nose-to-brain delivery of insulin enhanced by a nanogel carrier. J Control Release. 2018;270:23-36. https://doi.org/10.1016/j.jconrel.2017.11.040 PMid:29196041

[191] Sukumar UK, Bose RJC, Malhotra M, Babikir HA, Afjei R, Robinson E, et al. Intranasal delivery of targeted polyfunctional gold-iron oxide nanoparticles loaded with therapeutic microRNAs for combined theranostic multimodality imaging and presensitization of glioblastoma to temozolomide. Biomaterials. 2019;2018:119342. https://doi.org/10.1016/j.biomaterials.2019.119342 PMid:31326657 PMCid:PMC6663564

[192] Liu S, Yang S, Ho PC. Intranasal administration of carbamazepine-loaded carboxymethyl chitosan nanoparticles for drug delivery to the brain. Asian J Pharm Sci. 2018;13(1):72-81. https://doi.org/10.1016/j.ajps.2017.09.001 PMid:32104380 PMCid:PMC7032105

[193] Katare YK, Daya RP, Gray CS, Luckham RE, Bhandari J, Chauhan AS, et al. Brain targeting of a water-insoluble antipsychotic drug haloperidol via the intranasal route using PAMAM dendrimer. Mol Pharm. 2015;12(9):3380-8. https://doi.org/10.1021/acs.molpharmaceut.5b00402 PMid:26226403

[194] Md S, Khan RA, Mustafa G, Chuttani K, Baboota S, Sahni JK, et al. Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model. Eur J Pharm Sci. 2013;48:393-405. https://doi.org/10.1016/j.ejps.2012.12.007 PMid:23266466

[195] Muntimadugu E, Dhommati R, Jain A, Challa VGS, Shaheen M, Khan W. Intranasal delivery of nanoparticle encapsulated tarenflurbil: a potential brain targeting strategy for Alzheimer's disease. Eur J Pharm Sci. 2016;92:224-34. https://doi.org/10.1016/j.ejps.2016.05.012 PMid:27185298

[196] Taki H, Kanazawa T, Akiyama F, Takashima Y, Okada H. Intranasal delivery of camptothecin-loaded Tat-modified nanomicells for treatment of intracranial brain tumors. Pharmaceuticals. 2012;5:1092-102. https://doi.org/10.3390/ph5101092 PMid:24281259 PMCid:PMC3816654

[197] Muniswamy VJ, Raval N, Gondaliya P, Tambe V, Kalia K, Tekade RK. 'Dendrimer-cationized-albumin' encrusted polymeric nanoparticle improves BBB penetration and anticancer activity of doxorubicin. Int J Pharm. 2019;555:77-99. https://doi.org/10.1016/j.ijpharm.2018.11.035 PMid:30448308

[198] Qu Y, Li A, Ma L, Iqbal S, Sun X, Ma W, et al. Nose-to-brain delivery of disulfiram nanoemulsion in situ gel formulation for glioblastoma targeting therapy. Int J Pharm. 2021;597:120250. https://doi.org/10.1016/j.ijpharm.2021.120250 PMid:33486040

[199] Guo T, Guo Y, Gong Y, Ji J, Hao S, Deng J, et al. An enhanced charge-driven intranasal delivery of nicardipine attenuates brain injury after intracerebral hemorrhage. Int J Pharm. 2019;566:46-56. https://doi.org/10.1016/j.ijpharm.2019.05.050 PMid:31121211

[200] Mittal D, Md S, Hasan Q, Fazil M, Ali A, Baboota S, et al. Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route. Drug Deliv. 2014;23(1):130-9. https://doi.org/10.3109/10717544.2014.907372 PMid:24786489

[201] Jafarieh O, Md S, Ali M, Baboota S, Sahni JK, Kumari B, et al. Design, characterization, and evaluation of intranasal delivery of ropinirole-loaded mucoadhesive nanoparticles for brain targeting. Drug Dev Ind Pharm. 2014;41(10):1674-81. https://doi.org/10.3109/03639045.2014.991400 PMid:25496439

[202] Alsaidan OA, Elkomy MH, Zaki RM, Tulbah AS, Yusif RM, Eid HM. Brain targeting of venlafaxine via intranasal transbilosomes thermogel for improved management of depressive disorder. J Pharm Sci. 2024;113(11). https://doi.org/10.1016/j.xphs.2024.08.026 PMid:39216538

[203] Gonçalves J, Alves G, Carona A, et al. Pre-clinical assessment of the nose-to-brain delivery of zonisamide after intranasal administration. Pharm Res. 2020;37:74. https://doi.org/10.1007/s11095-020-02786-z PMid:32215749

[204] Baltzley S, Mohammad A, Malkawi AH, Al-Ghananeem AM. Intranasal drug delivery of olanzapine-loaded chitosan nanoparticles. AAPS PharmSciTech. 2014;15(6):1598-602. https://doi.org/10.1208/s12249-014-0189-5 PMid:25142821 PMCid:PMC4245419

[205] Baltzley S, Mohammad A, Malkawi AH, Al-Ghananeem AM. Intranasal drug delivery of olanzapine-loaded chitosan nanoparticles. AAPS PharmSciTech. 2014;15(6):1598-602. https://doi.org/10.1208/s12249-014-0189-5 PMid:25142821 PMCid:PMC4245419