UCP2 inhibition eliminates pancreatic β cell autoinflammation in T2DM with islet-mitochondrial sequential targeting nanomedicines

Zerun Liu, Wensheng Chen, Jinping Zhang, Ting Huang, Ying Hong, Tianjiao Zhao, Min Liu, Qiaohui Chen, Yongqi Yang, Shuya Wang, Jue Wang, Xiaohong Ying, Yiming Li, Qiong Huang () and Kelong Ai ()
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Zerun Liu: Central South University
Wensheng Chen: Central South University
Jinping Zhang: Central South University
Ting Huang: Central South University
Ying Hong: Central South University
Tianjiao Zhao: Central South University
Min Liu: Central South University
Qiaohui Chen: Central South University
Yongqi Yang: Central South University
Shuya Wang: Central South University
Jue Wang: Central South University
Xiaohong Ying: Central South University
Yiming Li: Central South University
Qiong Huang: Central South University
Kelong Ai: Central South University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Pancreatic β-cell dysfunction and mass loss are core pathologies of type 2 diabetes mellitus (T2DM), which are closely related to intense autoinflammation. However, the molecular mechanisms regulating β-cell autoinflammation remain unclear. Here, we show that STING is significantly elevated in T2DM β cells. We also clarify the key role of uncoupling protein 2 (UCP2), and reveal that interleukin-1β (IL-1β) drives β cells to produce autoinflammation through the UCP2/mtDNA/STING axis in T2DM. To inhibit UCP2 activity in vivo, we design a tailored nanomedicine, Mito-G, with sequential targeting from islets to β-cell mitochondria. Mito-G is a negatively charged ultra-small nanomedicine synthesized by polymerization of genipin (a potent UCP2 inhibitor) and glycine. It can specifically reach β cells and have a natural mitochondrial targeting. In this work, Mito-G effectively eliminates β-cell auto-inflammation by specifically inhibiting β-cell UCP2 activity in vivo, providing a paradigm for targeting autoinflammation of β cells to treat T2DM.

Date: 2025
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DOI: 10.1038/s41467-025-61883-y

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