A TGF-β1-Binding and Stem Cell-Homing Peptide Hydrogel Loaded with BMSC-Exosomes Enhances the Endogenous Repair of Surgically Induced Osteochondral Defects

Abstract

To address the poor self-repair capacity of experimental osteochondral defects and the inefficacy of conventional hydrogels, this study developed a biodegradable peptide hydrogel, Exos@TRM. This study used an acute surgically created osteochondral defect model in rats, which does not fully reproduce experimental cartilage defects or chronic human cartilage degeneration. Based on the RADA16 framework, this hydrogel incorporates a TGF-β1-binding peptide and a stem cell-recruiting motif, and is loaded with exosomes derived from bone marrow mesenchymal stem cells (BMSCs). In vitro experiments demonstrated that Exos@TRM effectively binds TGF-β1, promotes BMSC migration, and enables sustained exosome release for up to one week, thereby facilitating BMSC proliferation and chondrogenic differentiation. In a rat cartilage defect model, Exos@TRM reduced pro-inflammatory M1 macrophages, recruited endogenous TGF-β1 and BMSCs to the injury site, promoted chondrogenic differentiation at week 3, and achieved tissue regeneration resembling natural cartilage with functional mechanical properties by week 8. Mechanistic studies confirmed that the regenerative effects are TGF-β1-dependent, and comprehensive biosafety evaluation revealed no systemic toxicity. This study demonstrates that Exos@TRM achieves significant cartilage repair without exogenous cells or high-dose growth factors through synergistic immunomodulation, localized TGF-β1 recruitment, and stem cell homing, offering a clinically promising strategy for experimental cartilage defects.