Rational Engineering of a Mitochondrial‐Mimetic Therapy for Targeted Treatment of Dilated Cardiomyopathy by Precisely Regulating Mitochondrial Homeostasis

Abstract

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the most common indication for heart transplantation. Currently, there is still an unmet clinical need in effective therapies for DCM. Herein a mitochondrial‐mimetic therapy capable of efficiently targeting the heart, cardiomyocytes, and myocardial mitochondria as well as effectively regulating mitochondrial homeostasis for targeted treatment of DCM is reported. A bioactive conjugate TPT is first synthesized by integrating three functional moieties onto a scaffold, which can assemble into small‐size nanomicelles (i.e., TPTN). Intravenously delivered TPTN efficiently accumulates in the heart and mainly localizes in cardiomyocytes and myocardial mitochondria of DCM mice, thereby alleviating DCM. Mechanistically, TPTN inhibits intracellular oxidative stress, alleviates mitochondrial injury, improves mitochondrial dynamics, regulates mitochondrial oxidative phosphorylation, and reduces calpain‐1 and NLRP3 inflammasome activation, thus restoring mitochondrial homeostasis and inhibiting adverse cardiac remodeling. By packaging TPTN into outer mitochondrial membrane‐derived vesicles, a mitochondrial‐mimetic therapy is engineered, which displays significantly enhanced three‐level targeting capability to the heart, cardiac cells, and myocardial mitochondria, thereby affording notably potentiated therapeutic effects in DCM mice. Accordingly, the three‐level targeting mimetics is promising for targeted treatment of DCM. The findings provide new insight into rational design of precision therapies for mitochondrial dysfunction‐associated diseases.

Pathogenesis-Guided Rational Engineering of Nanotherapies for the Targeted Treatment of Abdominal Aortic Aneurysm by Inhibiting Neutrophilic Inflammation

“…Over the past decades, extensive studies have demonstrated that nanoparticle (NP)-based drug delivery is a highly effective strategy for targeted treatment of cardiovascular diseases, such as myocardial infarction, heart failure, atherosclerosis, and AAA, − by efficiently enhancing drug accumulation at diseased sites and simultaneously reducing nonspecific distribution. NPs can pass through the damaged endothelial barrier or be transported by inflammatory cells via a hitchhiking effect, thereby targeting vascular lesions.…”