Chitosan-based hydrogels for intranasal drug delivery in brain disease treatment

Introduction and clinical need for improved CNS delivery

Neurodegenerative and other brain disorders are a growing public health concern projected to affect increasing numbers of people in coming decades. A major impediment to effective therapy is the limited penetration of many therapeutics into the central nervous system due to the blood-brain barrier (BBB). Addressing delivery across or around the BBB is a key focus in contemporary CNS drug development.

Noninvasive approaches that bypass or reduce reliance on systemic BBB crossing are receiving attention. Among these, intranasal (IN) administration combined with nanoscale or hydrogel-based carriers is emerging as a promising route to improve direct delivery to the brain while enhancing patient acceptability.

Intranasal administration: nose-to-brain pathways and advantages

IN delivery permits access to the brain through neural pathways that connect the nasal cavity with the CNS. Transport occurs primarily via the olfactory pathway, which is identified as the principal route for nose-to-brain transfer, and secondarily via the trigeminal pathway.

Advantages of IN delivery highlighted in the source include its noninvasive nature and the potential to deliver molecules directly to the CNS without full systemic exposure. These characteristics make IN administration attractive for a range of CNS indications where rapid onset, reduced systemic side effects, or improved CNS targeting are desirable.

Chitosan-based hydrogels: material properties and mechanisms of action

Among intranasal platforms, chitosan (CS)-based hydrogels have garnered considerable interest. The review emphasizes several properties that make CS hydrogels suitable for IN brain delivery:

• Biocompatibility and biodegradability, supporting safety for mucosal application.
• Mucoadhesive properties that increase residence time in the nasal cavity, which can enhance drug uptake.
• The ability to enhance drug permeation by transiently modulating epithelial tight junctions, facilitating paracellular transport across the nasal epithelium.

These combined attributes allow CS hydrogels to act both as a sustained-release matrix and as a permeation enhancer, potentially improving the efficiency of nose-to-brain transport for a variety of therapeutic agents.

Applications of CS-based IN hydrogels in specific brain diseases

The review summarizes recent advances applying chitosan-based IN hydrogels across multiple brain disorders. Disease areas included are:

• Alzheimer’s disease (AD)
• Parkinson’s disease (PD)
• Depressive manifestations and mood disorders
• Cerebral ischemia
• Brain tumors
• Epilepsy and seizures
• Schizophrenia

For each condition, the review discusses how CS-based hydrogel formulations have been explored to improve CNS delivery of candidate therapeutics. The central premise is that increased nasal residence and permeation enhancement by CS hydrogels can improve target engagement in relevant brain regions compared with nonoptimized IN formulations or systemic routes.

Hydrogel design considerations and relationship to therapeutic performance

A key theme in the review is the relationship between hydrogel design parameters and therapeutic outcomes. Design considerations that influence performance include polymer concentration and molecular weight, crosslinking approach, rheological behavior (which affects sprayability and retention), drug loading and release kinetics, and mucoadhesive strength.

The review highlights that formulation attributes determine nasal residence time, the extent of epithelial modulation, and the drug release profile — all of which together shape CNS exposure and therapeutic effect. Therefore, rational optimization of CS hydrogel composition and physical properties is essential to translate preclinical efficacy into clinically meaningful CNS delivery.

Translational challenges and future perspectives for clinical development

While CS-based IN hydrogels show promising preclinical results across several CNS indications, the review outlines current translational challenges that must be addressed for clinical development. These include:

• The need for standardized preclinical evaluation methods that predict human nasal deposition, residence, and nose-to-brain transfer.
• Regulatory considerations for novel intranasal hydrogel platforms, including safety assessment of repeated mucosal exposure and long-term effects on nasal tissues.
• Challenges in scaling manufacturing while maintaining reproducible rheological and mucoadhesive properties.
• Gaps between preclinical animal models and human nasal anatomy and physiology that can complicate extrapolation of efficacy and safety.

The authors discuss future perspectives focused on overcoming these barriers to enable clinical translation of CS-based IN hydrogel systems for brain disease therapy.

Conclusion

The reviewed literature positions chitosan-based hydrogels as a promising intranasal platform for enhancing nose-to-brain delivery. Their biocompatibility, mucoadhesion, and permeation-enhancing effects make them attractive candidates for treating a range of CNS disorders, including AD, PD, mood disorders, ischemia, brain tumors, epilepsy, and schizophrenia. However, advancing these systems toward clinical use will require rigorous formulation optimization, standardized translational studies, and attention to regulatory and manufacturing challenges. The authors report no competing interests in the preparation of the review.