Engineered Cytokine‐Primed Extracellular Vesicles with High PD‐L1 Expression Ameliorate Type 1 Diabetes

Abstract Type 1 diabetes (T1D), which is a chronic autoimmune disease, results from the destruction of insulin‐producing β cells targeted by autoreactive T cells. The recent discovery that mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) function as therapeutic tools for autoimmune conditions has attracted substantial attention. However, the in vivo distribution and therapeutic effects of MSC‐EVs potentiated by pro‐inflammatory cytokines in the context of T1D have yet to be established. Here, it is reported that hexyl 5‐aminolevulinate hydrochloride (HAL)‐loaded engineered cytokine‐primed MSC‐EVs (H@TI‐EVs) with high expression of immune checkpoint molecule programmed death‐legend 1 (PD‐L1) exert excellent inflammatory targeting and immunosuppressive effects for T1D imaging and therapy. The accumulated H@TI‐EVs in injured pancreas not only enabled the fluorescence imaging and tracking of TI‐EVs through the intermediate product protoporphyrin (PpIX) generated by HAL, but also promoted the proliferative and anti‐apoptotic effects of islet β cells. Further analysis revealed that H@TI‐EVs exhibited an impressive ability to reduce CD4 + T cell density and activation through the PD‐L1/PD‐1 axis, and induced M1‐to‐M2 macrophage transition to reshape the immune microenvironment, exhibiting high therapeutic efficiency in mice with T1D. This work identifies a novel strategy for the imaging and treatment of T1D with great potential for clinical application.