Self-healing injectable N-succinyl chitosan-hyaluronic dialdehyde hydrogel with chitosan-coated...

Sustained intra-articular delivery is crucial for effective osteoarthritis (OA) therapy. We developed a dual-encapsulation platform by embedding kartogenin (KGN)-loaded chitosan-coated PLGA nanoparticles (PLGA-CS NPs) into a self-healing N-succinyl chitosan (NSC)-hyaluronic dialdehyde (HAD) hydrogel. Chitosan coating reversed the zeta potential of the NPs from -23.1 mV to +35.4 mV, enhancing electrostatic affinity for anionic cartilage. The NSC-HAD hydrogel rapidly gelled via Schiff-base linkages, maintained injectability, and retained self-healing capabilities following NPs incorporation. Rheology showed shear-thinning behavior; PLGA NPs increased the flow point (τ_f), whereas PLGA-CS NPs decreased τ_fvia stronger physical interactions. Hydrogels exhibited 60-80% recovery of G' after undergoing 1000% strain. KGN release reached ∼70% in 3 h from uncoated PLGA NPs, ∼40% with CS coating, and ∼ 18% over 28 days when embedded in hydrogel. The composite hydrogel exhibited high biocompatibility and supported mMSC viability in vitro. Based on the established release kinetics and structural integrity, this platform provides a tunable framework for sustained intra-articular drug delivery. This work serves as a physicochemical foundation for future biological studies aimed at evaluating its therapeutic retention and regenerative potential in osteoarthritis models.