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 () and Huilin Yang ()
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Shunyi Lu: The First Affiliated Hospital of Soochow University
Jie Cao: Soochow University
Zhuorun Song: The First Affiliated Hospital of Soochow University
Fei Gong: Soochow University
Peng Yang: The First Affiliated Hospital of Soochow University
Jun Ge: The First Affiliated Hospital of Soochow University
Yunfei He: The First Affiliated Hospital of Soochow University
Zhihui Han: Soochow University
Guanghui Hou: Soochow University
Zimin Zhang: The First Affiliated Hospital of Soochow University
Yuqi Yang: Soochow University
Yun Teng: The First Affiliated Hospital of Soochow University
Zengli Zhang: Soochow University
Jun Zou: The First Affiliated Hospital of Soochow University
Liang Cheng: Soochow University
Huilin Yang: The First Affiliated Hospital of Soochow University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63456-5

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