A scRNA-seq-guided gelsolin-functionalized gelatin methacryloyl platform integrating structural support and immunomodulation for osteoarthritis repair.

Abstract

Osteoarthritis (OA) is a debilitating degenerative joint disease characterized by the irreversible breakdown of articular cartilage and chronic synovial inflammation. Current clinical interventions are primarily palliative, failing to address the dual challenges of structural degradation and the hostile, inflammatory myeloid microenvironment. We developed Gelsolin-Gelma@PLX3397 (GGP) hydrogel successfully mimicked the viscoelastic properties of the natural extracellular matrix (ECM) while providing sustained, localized delivery of both structural proteins and small-molecule inhibitors which were identified in scRNA-seq. Dual-targeting approach not only arrested cartilage catabolism but also promoted the regeneration of functional hyaline-like cartilage rather than fibrocartilage. Our findings demonstrate that the GGP hydrogel provides a synergistic "structural support and molecular modulation" strategy. By re-engineering the joint's cellular landscape based on scRNA-seq-derived targets, this smart biomaterial platform offers a promising therapeutic avenue for the functional recovery and long-term repair of osteoarthritic joints.