A rationally designed polypeptide-based hybrid platform for targeted intranasal brain drug delivery.

Intranasal administration represents a safe and non-invasive route for drug delivery to the brain; however, clinical translation remains limited due to anatomical and physiological barriers. We present a modular hybrid biomaterial platform (NanoInBrain) that bypasses the blood-brain barrier via the olfactory route and enables central nervous system (CNS) drug delivery. The platform integrates a rationally designed polypeptide-based nanocarrier with a depot-forming hydrogel vehicle - a hyaluronic acid-poly-L-glutamate crosspolymer (HA-CP, Yalic®) - adapted from dermatological applications to enhance nasal mucosal retention and brain uptake. We engineered the nanocarrier system using star-shaped poly-L-glutamate (StPGA) architectures and systematically tuned physicochemical properties to optimize mucosal interaction and CNS diffusion. We introduced mucoadhesive and mucodiffusive functionalities via C-terminal odorranalectin (OL) conjugation, which improved nasal epithelium permeation through receptor-mediated mechanisms. Redox-responsive disulfide crosslinking (StPGA-CL-SS) further enhanced mucosal transport by enabling thiol-mediated anchoring to mucin glycoproteins, outperforming inert click-crosslinked variants. Ex vivo Franz diffusion studies and a nasal-mucosa-on-chip model demonstrated robust permeation, with in vivo imaging confirming brain distribution and intracellular uptake in neurons and microglia. Incorporation of HA-CP prolonged nasal residence (∼4 h) and increased total brain accumulation while being well-tolerated. This new platform combines architectural tunability, bioresponsive surface chemistry, and depot-mediated delivery in a scalable, biocompatible nose-to-brain delivery system with potential for treating neurological disorders.