Small extracellular vesicles produced from canine adipose-derived mesenchymal stem cells mitigate diabetes mellitus in streptozotocin-induced mice via β-cell revitalization.

Abstract

BACKGROUND: Small extracellular vesicles (sEVs) derived from mesenchymal stem cells are emerging as promising therapeutic agents in regenerative medicine. This study evaluated the therapeutic potential of sEVs from 3D-cultured canine adipose-derived mesenchymal stem cells in alleviating diabetes-induced systemic dysfunctions, focusing on their revitalizing, metabolic, and immunomodulatory properties. RESULTS: sEVs were identified as nanosized vesicles around 72 nm with a negative zeta potential (-21.15 mV) and a high particle concentration (1.07 × 10particles/mL). In vitro, sEVs (10particles/mL) protected INS-1 β-cells from etoposide (ETO)-induced cytotoxicity, enhancing cell viability, reducing apoptosis, and promoting recovery. Biodistribution analysis showed detectable levels in plasma for up to 24 h post-injection, suggesting sustained circulation and a potentially extended half-life compared to free therapeutic molecules. In streptozotocin (STZ)-induced diabetic mice, sEV treatment significantly improved glycemic control, enhanced glucose metabolism, and restored β-cell function, as reflected by improvements in HOMA-β, HOMA-IR, and QUICKI indices. Additionally, sEVs reduced systemic inflammation, restored immune homeostasis, and improved hematological, renal, and hepatic parameters. Double-dose sEV administration yielded the most pronounced therapeutic benefits, including enhanced glucose clearance and systemic recovery. CONCLUSIONS: sEVs exhibit robust revitalizing, metabolic, and immunomodulatory properties, effectively mitigating diabetes-related dysfunctions in vitro and in vivo. These findings highlight sEVs as a novel regenerative therapy for diabetes and its complications, providing a strong foundation for future clinical translation.