Living and Injectable Porous Hydrogel Microspheres Promoting Inflammation Modulation and Extracellular Matrix Remodeling for Intervertebral Disc Regeneration

Intervertebral disc degeneration (IDD) remains a major cause of chronic low back pain, with limited options for effective disease modification. The harsh microenvironment of the degenerated disc, characterized by excessive oxidative stress and inflammation, severely impairs the survival and reparative potential of transplanted stem cells. Here, we present an injectable, porous and multifunctional hydrogel microsphere platform (GMPB) designed to remodel the local niche and enhance stem cell-based disc regeneration. Microspheres were fabricated from a composite matrix of gelatin methacryloyl (GelMA) and chondroitin sulfate methacryloyl (ChsMA), conferring excellent cytocompatibility and cell-adhesive properties while mimicking key aspects of the native extracellular matrix. Incorporation of Prussian blue (PB) nanozymes endowed the microspheres with potent broad-spectrum reactive oxygen species (ROS) scavenging and anti-inflammatory activity, as evidenced by significantly higher DPPH, ABTS, and ·OH radical scavenging rates (all >63%) compared to controls. BMSCs-loaded GMPB (named GMPB (+BMSCs)) microspheres supported robust cell proliferation and protected transplanted cells against ROS-induced injury <i>in vitro</i>. <i>In vivo</i>, GMPB (+BMSCs) microspheres effectively preserved disc height, maintained matrix hydration (high T2-weighted MRI signal), and reduced histological degeneration, as indicated by lower Pfirrmann grades and improved extracellular matrix integrity. Collectively, these results highlight GMPB (+BMSCs) microspheres as a promising and versatile platform that synergistically integrates biomimetic support, redox modulation, and efficient cell delivery to establish a regenerative microenvironment for intervertebral disc repair and broader tissue engineering applications.