Abstract

Intervertebral disc degeneration (IVDD)-associated low back pain represents a substantial global health challenge with profound socioeconomic consequences. The dysregulated immune microenvironment in degenerated discs creates a hostile milieu that suppresses tissue repair. In this study, we engineered a hierarchical delivery platform where salidroside (SAL)-functionalized Prussian blue analogues (PBA) were electrostatically assembled into gelatin methacryloyl (GelMA) hydrogel microspheres. The system enables spatiotemporally controlled SAL release by combining PBA-mediated molecular loading with GelMA microsphere-based sustained delivery reservoirs. These functionalized hydrogel microspheres serve as fundamental regulatory units for the IVDD immune microenvironment, enabling minimally invasive treatment of IVDD. In vitro experiments revealed that functionalized hydrogel microspheres effectively promoted the activation of macrophages towards the reparative sentinel M2 phenotype, scavenged reactive oxygen species (ROS), and improved extracellular matrix (ECM) metabolism. In vivo studies further revealed that the functionalized hydrogel microspheres significantly restored intervertebral disc height, water content, and tissue structure in a rat IVDD model, while also enhancing ECM repair and suppressing inflammation. This study provides a novel therapeutic strategy for immunomodulation and tissue repair in degenerative disc diseases, with potential for future clinical translation.