Small Extracellular Vesicles From Human Amniotic Membrane Mesenchymal Stem Cells Rejuvenate Senescent β Cells and Cure Age‐Related Diabetes in Mice

ABSTRACT Targeting senescent pancreatic β‐cells represents a promising therapeutic avenue for age‐related diabetes; however, current anti‐senescence strategies often compromise β‐cell mass. In this study, human amniotic mesenchymal stem cell‐derived small extracellular vesicles (hAMSC‐sEVs) were identified as a novel intervention that can be used to effectively counteract cellular senescence and preserve β‐cell integrity. We aimed to systemically delineate the molecular mechanisms underlying hAMSC‐sEV‐mediated reversal of β‐cell senescence in age‐related diabetes. In oxidative stress‐induced and naturally aged β‐cell models, hAMSC‐sEVs mitigated senescence‐associated phenotypes, restored mitochondrial homeostasis, and enhanced insulin secretion capacity. In aged diabetic mice, administering these vesicles significantly ameliorated hyperglycemia, improved glucose tolerance, and reversed β‐cell functional decline by reducing senescent β‐cell populations, reinstating β‐cell identity markers, and suppressing senescence‐associated secretory phenotype (SASP) component production. Mechanistic investigations revealed that the miR‐21‐5p‐enriched hAMSC‐sEVs directly target the interleukin (IL)‐6 receptor α subunit (IL‐6RA), thereby inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation at tyrosine 705 and its subsequent nuclear translocation. This epigenetic modulation alleviated STAT3‐mediated transcriptional repression of the mitochondrial calcium uniporter (MCU), rectifying age‐related mitochondrial calcium mishandling and insulin secretion defects. Genetic ablation of MCU clearly established the central role of the miR‐21‐5p/IL‐6RA/STAT3/MCU axis in this regulatory cascade. Our findings reveal hAMSC‐sEVs as a novel senotherapeutic strategy for age‐related diabetes, elucidating the pivotal role of miR‐21‐5p‐driven epigenetic–mitochondrial calcium homeostasis in reversing β‐cell dysfunction, establishing a framework for targeting cellular senescence in metabolic disorders.