Sustained modulation of the inflammatory microenvironment for cartilage repair using an ROS-responsive hydrogel delivering CircSERPINE2-loaded exosomes

Osteoarthritis (OA) involves chronic inflammation and oxidative stress, both of which impair cartilage regeneration. To counteract these pathological processes, bone marrow mesenchymal stromal cell (BMSC)-derived exosomes have emerged as a promising therapy. These exosomes promote chondrogenesis and facilitate chemokine-guided cell homing. However, hostile microenvironments compromise their efficacy. This study developed a cell-free, ROS-responsive boronate-vinyl (BV) hydrogel platform encapsulating BMSC-derived exosomes overexpressing CircSERPINE2 (BV@cSERPINE2-Exo), which were isolated via ultracentrifugation from lentivirus-transduced BMSCs. This platform enables sustained microenvironmental modulation and functional cartilage regeneration. The hydrogel forms through dynamic boronate ester crosslinking between phenylboronic acid-modified poly γ-glutamic acid and polyvinyl alcohol (PVA). It exhibits rapid gelation, shear-thinning injectability, and potent ROS-scavenging capacity. ROS-triggered cleavage of the boronate ester bonds ensures controlled exosome release. In vitro, BV@cSERPINE2-Exo shifted LPS-stimulated macrophages from an M1 to M2 phenotype by decreasing iNOS and IL-1β levels and increasing Arg-1 and IL-10. Concurrently, the system protected chondrocytes from TNF-α-induced degeneration by downregulating MMP13 and restoring COL2A1, SOX9, and proteoglycan synthesis. In a rat patellar cartilage defect model, intra-articular injection of BV@cSERPINE2-Exo promoted deposition of cartilage-specific extracellular matrix and achieved near-complete hyaline cartilage-like repair within 8 weeks. This repair was superior to that in the BV hydrogel or unmodified exosome control groups. These results establish a smart, injectable biomaterial strategy that integrates precise ROS-responsive circRNA delivery with immunomodulation, offering a promising early intervention strategy for cartilage defect repair and the prevention of osteoarthritis progression.