Pyroptosis-responsive microspheres modulate the inflammatory microenvironment to retard osteoporosis in female mice
Shunyi Lu, Jie Cao, Zhuorun Song, Fei Gong, Peng Yang, Jun Ge, Yunfei He, Zhihui Han, Guanghui Hou, Zimin Zhang, Yuqi Yang, Yun Teng, Zengli Zhang, Jun Zou, Liang Cheng, Huilin Yang
Abstract
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) that exploit pyroptosis blockade and hydrogen-mediated inflammation regulation for osteoporosis treatment. This porous microsphere scaffold is implanted into bone defects to achieve the sustained release of hydrogen gas, magnesium ions (Mg2+), and dimethyl fumarate (DMF). DMF act by activating the nuclear factor erythroid-related factor 2 to prevent osteoblast pyroptosis, and combine with the antioxidant effects of hydrogen, effectively remodel the inflammatory microenvironment and create favorable conditions for the restoration of bone homeostasis. Mg2+ further expedite bone tissue repair. These results demonstrate that the GelMa/Mg/DMF MS effectively reverse inflammatory microenvironments both in vivo and in vitro, resulting in significant tissue repair. These results suggest the combination of hydrogen therapy and pyroptosis blockade as a potential therapeutic strategy. Osteoporosis was revealed to pyroptosis-related inflammation. Here, the authors show multifunctional microsphere can retard osteoporosis by restoring bone homeostasis thorough pyroptosis blockade and hydrogen-mediated modulation of inflammation.