Dynamic Hydrazone-Crosslinked Hyaluronic Acid Hydrogels with Dual-Responsive Nanoparticles for Controlled Hydrophobic Drug Release

Abstract Many hydrogel-based drug delivery systems suffer from poor release control, particularly undesirable initial burst release, limiting sustained delivery. Here, we developed a dual stimuli-responsive hyaluronic acid (HA) hydrogel-nanoparticle system to regulate release through coordinated matrix- and carrier-level responsiveness. Aldehyde-functionalized HA (HA-Ald) was crosslinked with a disulfide-containing hydrazide linker, forming dynamic hydrogels with reversible hydrazone bonds and redox-cleavable disulfide linkages. Nile Red-loaded nanoparticles (NR-NPs), composed of a light- and redox-responsive triblock copolymer containing disulfide linkages and terminal coumarin groups, were incorporated as model drug carriers. Reductive conditions simultaneously triggered hydrogel degradation and nanoparticle destabilization through shared disulfide chemistry, while UV light (365 nm) provided an orthogonal trigger for nanoparticle-mediated release. Fluorescence studies revealed an initial increase in NR intensity due to migration into hydrophobic domains, followed by gradual decline from network degradation and dye diffusion. These results indicate that the coordinated self-healing hydrogel-nanoparticle system improves release control while reducing burst release.