Design of a spermine-β-cyclodextrin functionalized gelatin nanoaggregate hydrogel for nose-to-brain delivery of...

Rapid mucociliary clearance and limited permeability across biological barriers remain major challenges for efficient nose-to-brain delivery of donepezil (DNP). Herein, we report a rationally engineered biodegradable gelatin hydrogel in which chemically conjugated spermine-β-cyclodextrin (SPM-β-CD) nanoaggregates were integrated to enhance intranasal nose-to-brain delivery of donepezil. Gelatin served as a biodegradable hydrogel matrix, while β-cyclodextrin provided host-guest inclusion sites for efficient donepezil encapsulation and spermine promoted supramolecular nanoaggregate formation within the polymer network. The hydrogel was synthesized through EDC/NHS-mediated crosslinking, generating a highly interconnected hierarchical architecture that regulated swelling behavior, structural stability, hydrolytic biodegradation, and diffusion-controlled drug release. Consequently, the optimized formulation (DNP/F-GHyd2) exhibited sustained DNP release together with pronounced free radical scavenging activity associated with the functional biomaterial components. In vivo pharmacokinetic evaluation in Sprague-Dawley rats showed significantly enhanced brain accumulation of DNP following intranasal administration of DNP/F-GHyd2 compared with free DNP solution, with brain maximum concentration (C _max) values of 0.059 ± 0.006 µg mL^-1 and 0.024 ± 0.005 µg mL^-1, respectively. Histopathological assessment further confirmed the biocompatibility of the developed hydrogel system with no detectable tissue alterations in brain sections. Collectively, these findings establish a clear structure-property-function relationship, demonstrating that chemically engineered SPM-β-CD nanoaggregates function as molecular regulators of gelatin hydrogel architecture. To the best of our knowledge, this study is the first to report a chemically engineered SPM-β-CD nanoaggregate gelatin hydrogel that utilizes supramolecular nanoaggregate engineering for sustained intranasal delivery of donepezil.