Mitochondria-rich cytochalasomes as an intravenously deliverable vesicle platform for ischemic heart disease

Poor organelle viability and rapid immune clearance limit mitochondrial transplantation for ischemic disease. Here, we engineer mitochondria-rich cytochalasomes (MRCs) as an intravenously deliverable vesicle platform. MRCs are generated through cytoskeletal remodeling in mesenchymal stem cells. They encapsulate functional mitochondria, protecting them from extracellular stressors and inheriting immunomodulatory proteins, which reduce macrophage phagocytosis by more than sixfold. Mechanistically, MRCs do not fuse with the host mitochondrial network but instead are trafficked to lysosomes and trigger protective autophagy-lysosomal response. In a murine myocardial ischemia/reperfusion (I/R) model, a single intravenous injection of MRCs reduced infarct size by 52% and preserved cardiac function for up to 28 days, whereas isolated mitochondria were ineffective. This work positions MRCs as a promising intravenously deliverable vesicle platform for ischemic heart disease and reveals a non-fusogenic mechanism.