Spatiotemporal Core–Shell Microspheres Enable Hydrogen‐Mediated Redox Priming and Kartogenin‐Induced Cartilage Regeneration for Osteoarthritis Bio‐Rescue

ABSTRACT The effective management of osteoarthritis (OA) remains a formidable clinical challenge due to a chronically inflamed joint microenvironment and the limited self‐regenerative capacity of articular cartilage. To address these barriers, we developed an ultrasound‐responsive core–shell microsphere platform engineered via a customized microfluidic capillary device. This system features a kartogenin (KGN)‐loaded poly(lactic‐co‐glycolic acid) (PLGA) core encapsulated within a sodium alginate shell enriched with tin disulfide (SnS) nanosheets (SSN). Following intra‐articular injection, non‐invasive ultrasound stimulation triggers the localized SSN to generate low‐concentration hydrogen gas (H 2 ). This in situ H 2 generation rapidly scavenges excess reactive oxygen species to restore redox homeostasis, thereby mitigating mitochondrial dysfunction and preserving chondrocyte viability. Consequently, this targeted antioxidative intervention suppresses pro‐inflammatory cytokine secretion and polarizes synovial macrophages toward a pro‐regenerative M2 phenotype. Within this newly stabilized microenvironment, the sustained release of KGN from the PLGA core successfully reverses extracellular matrix metabolic imbalances to promote cartilage repair. In a rat model of OA, this dual‐functional, spatiotemporally controlled platform profoundly halted joint degeneration and preserved histological cartilage integrity. Collectively, this ultrasound‐triggered core–shell microsphere system offers a highly promising, disease‐modifying strategy for comprehensive OA therapy.