Abstract: Thermosensitive hydrogels have emerged as a transformative platform for nose-to-brain drug delivery, allowing a non-invasive approach to bypass the blood-brain barrier and ad-dress the growing worldwide burden of neurological diseases. This article discusses innovations and bottlenecks in thermosensitive polymer hydrogel systems for intranasal central nervous sys-tem (CNS) targeting. Recent breakthroughs include composite polymer systems such as chitosan-poloxamer blends and PNIPAM-PEG copolymers that provide accurate lower critical solution temperature control (32-34°C), increased mucoadhesion, and sustained release. Optimized formu-lations have demonstrated improved drug loading, prolonged nasal residence, and substantial en-hancement of brain exposure and targeting efficiency in preclinical studies. Nanotechnology inte-gration-which includes lipid nanocapsules, polymeric micelles, and ligand-functionalized carri-ers-further improves targeting specificity, while multi-responsive structures (pH, enzyme, and re-dox-sensitive) enable on-demand release. Despite these gains, translation is hindered by batch variability, temperature-dependent stability, limited hydrophilic drug loading, variable gelation kinetics, and a lack of validated human-relevant preclinical models. Regulatory pathways also lack uniform evaluation standards, impeding scale-up and GMP standardization. Future progress will depend on integrating predictive human organoid and physiologically based pharmacokinetic platforms, rigorous long-term safety frameworks, and strategic intellectual property management to convert laboratory discoveries into clinically feasible therapies for Alzheimer’s, Parkinson’s, epilepsy, and related CNS disorders.
Kumar et al. (2026) studied this question.