Hydrogels-based nasal sprays for nose-to-brain delivery: Formulation strategies, composite systems, and performance optimization.

Nose-to-brain drug delivery has been extensively investigated for central nervous system therapy due to its ability to bypass the blood-brain barrier and reduce systemic exposure. Among available intranasal dosage forms, hydrogels-based nasal sprays have emerged as a promising platform due to their ability to prolong nasal residence and enable controlled drug release. This review, from the perspective of formulation-oriented design of hydrogel nasal sprays, focuses on composite systems, spray performance, and drug specific strategies in addition to material selection. Recent advances highlight the integration of nanocarriers within hydrogel matrices to achieve coordinated control of drug protection, release behavior, and mucosal retention, effectively addressing key challenges in nasal drug delivery. Meanwhile, key spray-related critical quality attributes, including viscosity, droplet size, and spray dynamics, are extensively reviewed with respect to their effects on nasal cavity deposition and nose-to-brain delivery efficiency. Finally drug specific formulation design is discussed as a central factor guiding strategies for small molecules, macromolecules, and oligonucleotide drugs. Overall, this review proposes a formulation-oriented and systems-level framework to guide the rational development and clinical translation of hydrogels-based nasal spray dosage forms for nose-to-brain drug delivery.