Longqing Xia,1 Mengmeng Yang,1 Nan Zang,1– 4 Jia Song,1– 4 Jun Chen,1– 4 Huiqing Hu,1 Kewei Wang,1 Yingyue Xiang,1 Jingwen Yang,1 Liming Wang,1 Ying Zou,1 Xiaoyu Lv,1 Xinguo Hou,1– 4 Li Chen1– 4 

1Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China; 2Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People’s Republic of China; 3Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, People’s Republic of China; 4Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, People’s Republic of China

Correspondence: Li Chen, Department of Endocrinology, Qilu Hospital of Shandong University, Shandong, People’s Republic of China, Email chenli3@email.sdu.edu.cn

Background: The depletion of β cell mass is widely recognized as a significant contributor to the progression of type 2 diabetes mellitus (T2DM). Exosomes derived from mesenchymal stem cells (MSC-EXOs) hold promise as cell-free therapies for treating T2DM. However, the precise effects and mechanisms through which MSC-EXO affects β cell function remain incompletely understood, and the limited ability of MSC-EXO to target β cells and the short blood circulation time hampers its therapeutic effectiveness.
Methods: The effects of MSC-EXO were investigated in T2DM mice induced by a high-fat diet combined with STZ. Additionally, the high glucose-stimulated INS-1 cell line was used to investigate the potential mechanism of MSC-EXO. Michael addition reaction-mediated chemical coupling was used to modify the surface of the exosome membrane with a β-cell-targeting aptamer and polyethylene glycol (PEG). The β-cell targeting and blood circulation time were evaluated, and whether this modification enhanced the islet-protective effect of MSC-EXO was further analyzed.
Results: We observed that the therapeutic effects of MSC-EXO on T2DM manifested through the reduction of random blood glucose levels, enhancement of glucose and insulin tolerance, and increased insulin secretion. These effects were achieved by augmenting β cell mass via inhibiting nuclear factor erythroid 2–related factor 2 (NRF2)-mediated ferroptosis. Mechanistically, MSC-EXOs play a role in the NRF2-mediated anti-ferroptosis mechanism by transporting active proteins that are abundant in the AKT and ERK pathways. Moreover, compared to MSC-EXOs, aptamer- and PEG-modified exosomes (Apt-EXOs) were more effective in islet protection through PEG-mediated cycle prolongation and aptamer-mediated β-cell targeting.
Conclusion: MSC-EXO suppresses NRF2-mediated ferroptosis by delivering bioactive proteins to regulate the AKT/ERK signaling pathway, thereby improving the function and quantity of β cells. Additionally, Apt-EXO may serve as a novel drug carrier for islet-targeted therapy.

Keywords: exosome, type 2 diabetes mellitus, β-cell-targeting, polyethylene glycol modification, ferroptosis