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, Kelong Ai
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. The relationship between pancreatic β-cell dysfunction and autoinflammation in T2DM is unclear. Here, the authors show the key role of a UCP2/mtDNA/STING axis in the IL-1β induced autoinflammation cycle in T2DM and develop Mito-G, a highly efficient mitochondria targeting nanodrug to treat T2DM.