Self-supported DNA hydrogel facilitates microenvironment remodeling and cartilage repair to prevent osteoarthritis progression via an ambidextrous strategy.

Osteoarthritis (OA), a prevalent degenerative joint disease, currently lacks effective therapeutic options beyond symptomatic relief. Persistent inflammation and impaired cartilage repair accelerate the disease progression. The enzyme inducible nitric oxide synthase (iNOS) contributes to OA by producing nitric oxide (NO), which intensifies inflammation and inhibits cartilage regeneration. Traditional iNOS inhibitors have demonstrated limited efficacy due to inadequate targeted release and uncoordinated control over inflammation. In this study, we developed a self-supported DNAzyme-based DNA hydrogel using rolling circle amplification (RCA) technology to deliver iNOS-targeting DNAzymes and bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) in response to inflammation. The hydrogel incorporates triglycerol monostearate nanoparticles (TGMS NPs), which degrade under high matrix metalloproteinase (MMP) levels in OA joints, thereby triggering the release of the DNAzymes and exosomes with precision. This targeted delivery modulates the inflammatory microenvironment by reducing pro-inflammatory NO production and supports chondrogenesis by promoting M2 macrophage polarization. In vitro and in vivo analyses reveal that the hydrogel significantly reduces inflammatory cytokine levels, enhances chondrocyte proliferation, and restores extracellular matrix integrity, ultimately slowing OA progression. This smart hydrogel offers a promising ambidextrous strategy for microenvironment modulation and cartilage regeneration, potentially advancing OA treatment.