Enhanced Elastic Multifunctional Dual-Network Hydrogel Microspheres for the Treatment of Intervertebral Disc Degeneration through Inflammation Modulation and Apoptosis Inhibition

Modulating the local inflammatory environment and restoring nucleus pulposus cell (NPC) function are essential strategies for mitigating IVDD. In this study, a microgel-based delivery system for microRNA therapeutics, termed POCM@MCCP (PMCCP), was developed. The system employs dual-network hydrogel microspheres composed of chitosan, citric acid, and poly(vinyl alcohol) (CCP), further functionalized with metal-phenolic networks (MPNs) formed from strontium ions (Sr 2 + ) and epigallocatechin gallate (EGCG). This microgel enables dynamic, stimulus-responsive loading of phenylboronic acid-modified oxidized hyaluronic acid (PBA-oHA)-coated miR-155/chito-oligosaccharide (COS) complexes (POCM) through boronate ester linkages. The mechanical elasticity and stability of the CCP microspheres support the consistent and prolonged release of miR-155 even under mechanical compression. Incorporation of MPNs further endows the system with the ability to modulate and suppress the inflammatory microenvironment. In oxidative microenvironments, the boronate bonds cleave, triggering the release of POCM and its subsequent CD44 receptor-mediated internalization by NPCs. Subsequently, miR-155 and COS are released within the acidic intracellular space, modulating the Bcl-2/Bax/Caspase-3 signaling cascade and scavenging intracellular ROS, respectively. Both in vitro and in vivo IVDD models demonstrated that this multifunctional platform effectively suppresses inflammation and restores NPC function, highlighting its potential as a promising therapeutic strategy for IVDD.