Alleviation of diabetic cardiomyopathy via preventing VCAM1-positive cells from senescence by engineered nanovesicles.

Diabetic cardiomyopathy (DCM) involves progressive cardiac dysfunction driven by vascular endothelial injury and cellular senescence. However, precisely targeting pre-senescent cells remains a major therapeutic challenge. Herein, through single-cell RNA sequencing of diabetic mouse hearts, we identified VCAM1 -positive (VCAM1+) cells as a distinct pre-senescent endothelial population. Both scRNA-seq and subsequent immunofluorescence analyses confirmed the concurrent upregulation of cGAS-STING signaling within this VCAM1 + population, nominating it as a critical therapeutic target for early intervention. To specifically deliver a STING antagonist to these cells, we developed a biomimetic delivery platform based on engineered HEK293T cell-derived nanovesicles. Through lipidomic analysis, we reprogrammed the vesicle membrane composition to mimic that of endothelial cells, thereby creating nanovesicles with enhanced membrane fusogenic properties (F-NVs). After loading with H151, a potent STING pathway inhibitor that acts by inhibiting STING phosphorylation, the resulting F-NVs-tVCAM1@H151 efficiently targeted VCAM1 + pre-senescent cells, potently inhibited their transition into a senescent state, and significantly reduced the overall senescent burden in the diabetic heart. Consequently, this targeted strategy alleviated cardiac microvascular injury and markedly improved cardiac function in diabetic mice. This work identifies VCAM1 as a novel pre-senescent marker and demonstrates membrane lipid engineering as an effective approach for targeted nanovesicle delivery, offering a precise targeted therapeutic paradigm for DCM.