Pyroptosis-responsive microspheres modulate the inflammatory microenvironment to retard osteoporosis in female mice

The treatment of osteoporosis and related bone defects remains challenging. This study identifies pyroptosis driven inflammation as a key disruptor of bone homeostasis. To address this, we develop a magnesium gelatin composite microsphere scaffold (GelMa/Mg/DMF MS). This porous system enables sustained release of hydrogen gas (H2), magnesium ions (Mg2+), and the pyroptosis inhibitor dimethyl fumarate (DMF) within bone defects. DMF inhibits the nuclear factor erythroid-related factor 2 pathway, preventing osteoblast pyroptosis. Combined with H2 antioxidant effects, this remodels the inflammatory microenvironment, restoring bone homeostasis. Mg2+ further accelerates bone repair. Results demonstrate that the GelMa/Mg/DMF MS effectively reverse inflammatory microenvironments both in vivo and in vitro, driving significant tissue repair. This strategy confirms the therapeutic synergy of hydrogen therapy and pyroptosis blockade against osteoporosis. Composed of Food and Drug Administration-approved components, the scaffold holds high clinical translation potential for future applications.