ZIF-8-Based Nanocarrier for Targeted Delivery of Dimethyl Malonate in Osteoarthritis Therapy

Osteoarthritis (OA) is a prevalent chronic joint disease characterized by progressive cartilage degradation, synovial inflammation, and subchondral bone remodeling. Current pharmacotherapies are limited by poor targeting, low bioavailability, and systemic side effects. Here, we developed a zinc-based metal–organic framework (ZIF-8) loaded with dimethyl malonate (DM), a succinate dehydrogenase inhibitor, for targeted OA therapy. The DM@ZIF-8 nanocomposites were synthesized via a one-step coprecipitation method and characterized using TEM, FT-IR, UV-Vis, DLS, and zeta potential measurements. The in vitro drug release profile showed pH-responsive behavior, with accelerated release under acidic conditions mimicking the inflammatory microenvironment. Cell viability and hemolysis assays demonstrated good biocompatibility. Macrophage polarization studies revealed that DM@ZIF-8 promoted M2 polarization, as indicated by increased CD206 and TGF-β expression and decreased CD86 and iNOS levels. In an OA rat model, DM@ZIF-8 significantly improved joint structure, reduced cartilage damage, and modulated inflammatory cytokines (increased IL-10/TGF-β, decreased TNF-α/iNOS). Histological and biochemical analysis confirmed no obvious systemic toxicity. Our findings suggest that DM@ZIF-8 is a promising nanoplatform for targeted OA therapy with improved efficacy and safety. In summary, this study utilizes ZIF-8 nanocarriers to deliver succinate dehydrogenase inhibitor (DM) for modulating macrophage polarization in the treatment of osteoarthritis.