A biomimetic mesenchymal stem cell membrane-coated nanodelivery system attenuates cardiac fibrosis by restoring mitochondrial homeostasis.

Abstract

Myocardial fibrosis is a critical pathological endpoint in heart failure, yet effective targeted therapies remain lacking. Dysregulation of mitochondrial dynamics, particularly Drp1-mediated excessive fission, drives cardiomyocyte dysfunction and pro-fibrotic signaling. Mdivi-1 is a selective Drp1 inhibitor, but suffers from poor solubility, lack of cardiac targeting, and potential systemic toxicity. To address these limitations, we developed a mesenchymal stem cell membrane-coated biomimetic nanodelivery system (MM@NPs/Mdivi-1) with high drug loading capacity and pH-responsive release properties. In vitro, MM@NPs/Mdivi-1 enhanced cellular uptake in injured cardiomyocytes, restored mitochondrial network integrity and membrane potential, and suppressed Drp1 phosphorylation. In an isoproterenol-induced murine cardiac fibrosis model, the system achieved cardiac-specific enrichment, improved cardiac function, reduced collagen deposition, and restored mitochondrial ultrastructure. Mechanistically, transcriptomics combined with functional rescue experiments revealed that its anti-fibrotic effects were dependent on FUNDC1-mediated mitophagy activation. Collectively, MM@NPs/Mdivi-1 effectively attenuates myocardial fibrosis by restoring mitochondrial homeostasis, offering a promising targeted nanotherapeutic strategy for heart failure.