Myocardial delivery of miR30d with peptide-functionalized milk-derived extracellular vesicles for targeted treatment of hypertrophic heart failure.

miR30d has been shown to reverse cardiac hypertrophy. However, effective delivery of miR30d to the heart is challenging. Here, we engineered milk-derived extracellular vesicles (mEVs) by surface functionalization with an ischemic myocardium-targeting peptide (IMTP) and encapsulated miR30d to develop a formulation, the miR30d-mEVsIMTP, enabling targeted delivery of miR30d to the injured heart. In vitro, the miR30d-mEVsIMTP can be effectively internalized by hypoxia-induced H9C2 cells via the endo-lysosomal pathway. In the isoproterenol (ISO)-induced cardiac hypertrophy mice, more miR30d-mEVsIMTP accumulated in cardiac tissue than miR30d-mEVs following intravenous administration. As a result, miR30d-mEVsIMTP alleviated cardiac hypertrophy and rescued cardiac function in three murine models of hypertrophic heart failure. Mechanistically, we identified GRK5 as an unprecedented target of miR30d in cardiac hypertrophy. Taken together, our findings demonstrate that mEVs conjugated with IMTP effectively deliver miR30d to the pathological heart and thereby ameliorating cardiac hypertrophy and dysfunction via targeting GRK5-mediated signaling pathways.