Polydopamine as a biocompatible and precise mitochondrial targeted therapeutic platform for reversing myocardial...

Targeting mitochondria offers a compelling strategy for treating a broad spectrum of major diseases. However, the development of specific and biocompatible mitochondrial delivery vectors remains a key obstacle. In this study, we identified polydopamine (PDA)-a highly biocompatible material with inherent reactive oxygen species (ROS)-scavenging capabilities-as a naturally mitochondria-targeting biomaterial. PDA exhibits strong binding affinity to several critical outer mitochondrial membrane proteins, including the voltage-dependent anion channel and translocases of the outer membrane, conferring it with intrinsic mitochondrial tropism. As a proof-of-concept, we constructed a special channel PDA nanocapsule (CP) to encapsulate the mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A (CsA), forming CPC. In a myocardial ischemia-reperfusion injury (MIRI) model, intravenously administered CPC selectively accumulated in infarcted myocardium and was highly enriched within cardiomyocyte mitochondria. CPC not only suppressed the mitochondrial ROS burst but also released CsA in a controlled manner via its specialized channels, inhibiting mPTP opening. This intervention prevented cardiomyocyte apoptosis and attenuated the subsequent inflammatory cascade by blocking the cGAS-STING pathway. Remarkably, CPC nearly reversed the pathological effects of MIRI, with efficacy surpassing that of CsA alone. This innovative mitochondrial-targeting approach offers a versatile platform for mitochondrial repair and presents new therapeutic avenues for a range of diseases associated with mitochondrial injury.