Reactive Oxygen Species-Responsive Hydrogel Microspheres Loaded with Epigallocatechin Gallate for Effective Osteoarthritis Therapy.

Osteoarthritis (OA) is characterized by cartilage degeneration and inflammation. In this study, we developed a reactive oxygen species (ROS)-responsive water-in-hydrogel microsphere system (EGCG-TSPBA@WHM) for targeted delivery of epigallocatechin gallate (EGCG). The system exhibited sustained release, excellent biocompatibility, and cartilage-targeting capability via WYRGRL peptide modification. In vitro experiments demonstrated that EGCG-TSPBA@WHM reduced ROS, suppressed inflammation, and protected extracellular matrix integrity in chondrocytes. In vivo studies showed that the microspheres significantly alleviated cartilage degeneration and improved joint function in OA mouse models. Integrated single-cell transcriptomics and metabolomics revealed that the therapeutic effect involved the upregulation of Tomm70 and restoration of ER-mitochondria-calcium homeostasis. Functional experiments confirmed that Tomm70 overexpression mimicked and its silencing abrogated the therapeutic benefits of EGCG-TSPBA@WHM. This study presents a promising strategy for OA treatment and expands the clinical potential of natural compounds through smart delivery systems.