Mesenchymal stem cell-derived small extracellular vesicles alleviate LPS-induced myocardial injury via the microRNA-23a-3p/BNIP3L pathway.

Sepsis-induced myocardial injury is a critical condition with limited therapeutic options. This study investigates the therapeutic potential of mesenchymal stem cell (MSC)-derived small extracellular vesicles (MEx) in lipopolysaccharide (LPS)-induced myocardial injury in rat model and explores the underlying molecular mechanisms. We established a sepsis model using LPS and treated it with Mex, which were isolated and loaded with microRNA-23a-3p mimics (MEx-miR-23a-3p). Our findings demonstrate that MEx-miR-23a-3p significantly reduces LPS-induced secretion of B-type natriuretic peptide (BNP), cardiac troponin T (cTnT), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in H9C2 cells and rat serum. Furthermore, MEx-miR-23a-3p attenuates LPS-mediated proliferation impairment, apoptosis, and fibrosis in cardiomyocytes, and enhances migration and tube formation capacity in LPS-injured rat vascular endothelial cells. Notably, the protective role of MEx-miR-23a-3p against LPS-induced cardiomyocyte dysfunction was abolished upon pretreatment with GW4869, an inhibitor of exosome biogenesis and release. Mechanistically, miR-23a-3p directly binds to the 3' untranslated region of BNIP3L mRNA, downregulating its expression. Silencing BNIP3L mimics these protective effects by reducing LPS-induced cardiomyocyte apoptosis. These results suggest that MEx may attenuate myocardial injury, inflammation, and apoptosis in septic rats, possibly through MEx-mediated delivery of miR-23a-3p and modulation of the BNIP3L signaling axis. These results provide preliminary evidence supporting the therapeutic potential of MEx as a candidate intervention for sepsis-induced cardiomyopathy.