Spatiotemporally controlled H2S delivery regulates ECM remodeling for osteoarthritis therapy

Osteoarthritis (OA) is a degenerative joint condition marked by gradual breakdown of the cartilage extracellular matrix (ECM) within an acidic, oxidative articular microenvironment. Supplementary intervention targeting localized hydrogen sulfide (H 2 S) deficiency in progressing articular inflammation zones offers a promising therapeutic approach. However, achieving precise control over H 2 S delivery in terms of both location and timing remains a significant challenge. In this study, we present a core-shell nanoplatform, mPADT@PEG, engineered for dual-responsive H 2 S release to remodel the ECM. The nanocarrier is activated by the acidic environment within OA lesions, ensuring localized drug accumulation. Additionally, near-infrared (NIR) irradiation triggers H 2 S release, allowing for precise dose modulation. Mechanistically, spatiotemporal H 2 S delivery effectively scavenges reactive oxygen species (ROS), which inhibits the MAPK/p38 signaling pathway, thereby restoring chondrocyte anabolic-catabolic balance and preventing ECM degradation. In vivo experiments in OA models show that this approach reduces inflammation, enhances ECM remodeling, and preserves cartilage integrity. This study demonstrates a precision therapeutic paradigm. Our findings highlight the potential of spatiotemporal H 2 S modulation as a targeted nanomedicine strategy to slow OA progression.