Injectable microenvironment-responsive hydrogels encapsulating engineered NF-κB-targeting circular RNA for osteoarthritis therapy

Osteoarthritis (OA) is a prevalent joint disease characterized by cartilage degeneration and an imbalance in subchondral bone homeostasis. Effective topical treatment of OA remains challenging due to the insufficient long-term efficacy, instability, and rapid clearance of therapeutic agents. In this study, we targeted the overactive NF-κB signaling in OA by introducing a P65 super repressor gene (srIκBα) as a circular RNA (circRNA), encapsulated within modified lipid nanoparticles (LNPs), and embedded in a silk fibroin composite hydrogel (SHC) cross-linked with matrix metalloproteinase (MMP)-sensitive substrate peptides. Consequently, we developed an environment-responsive intelligent drug delivery system, namely, circ-srIκBα@LNP-SHC, and the performance of this system was evaluated both in vitro and in vivo. It demonstrated potent targeting effects on chondrocytes and fibroblast-like synoviocytes (FLS) in vitro, with significantly inhibiting NF-κB signaling. In an OA rat model, circ-srIκBα@LNP-SHC exhibited superior anti-OA efficacy and cartilage repair capability, and markedly suppressed the expression of OA-related inflammatory mediators and matrix-degrading enzymes, and reversed the OA-associated gene expression profile. The therapeutic effect was further validated using human OA cartilage cultured ex vivo. In conclusion, our environmentally responsive drug delivery system based on circ-srIκBα shows significant potential for OA treatment, offering improved cell specificity, stability, and low immunogenicity, which may provide a novel strategy for OA management.