UCP2 inhibition eliminates pancreatic β cell autoinflammation in T2DM with islet-mitochondrial sequential targeting nanomedicines
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.
Authors
- Kelong Ai (ORCID: https://orcid.org/0000-0002-9863-8963)
- Qiaohui Chen (ORCID: https://orcid.org/0000-0002-0681-2996)
- Ying Hong (ORCID: https://orcid.org/0009-0004-9503-5712)
- Qiong Huang (ORCID: https://orcid.org/0000-0002-0570-5961)
- Ting Huang (ORCID: https://orcid.org/0000-0001-8751-639X)
- Tianjiao Zhao (ORCID: https://orcid.org/0000-0002-3675-2840)
- Min Liu (ORCID: https://orcid.org/0000-0003-4779-8489)
- Yiming Li (ORCID: https://orcid.org/0000-0003-4602-3905)
- Yongqi Yang (ORCID: https://orcid.org/0000-0003-4407-1807)
- Shuya Wang (ORCID: https://orcid.org/0000-0001-8766-5862)
- Jinping Zhang (ORCID: https://orcid.org/0000-0001-5537-5131)
- Wensheng Chen (ORCID: https://orcid.org/0000-0002-2853-8422)
- Zerun Liu (ORCID: https://orcid.org/0009-0005-5718-5952)
- Xiaohong Ying
- Jue Wang (ORCID: https://orcid.org/0000-0001-8149-1566)
Institutions
- Central South University (CN)
- National Clinical Research (US)
- Xiangya Hospital Central South University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1038/s41467-025-61883-y
- Citations
- 10
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 20.06
Funders
- National Natural Science Foundation of China
- Central South University
- Xiangya Hospital, Central South University
- Fundamental Research Funds for the Central Universities