Mitochondrial Delivery of Molecular Drugs Bypassing Endocytosis

Abstract Although mitochondria are potential therapeutic target for various diseases, the targeted delivery of drugs to mitochondria is challenging. Conventional carrier-based drug delivery utilizes an endocytic uptake pathway that results in partial and delayed mitochondrial targeting due to complicated endosomal trafficking followed by endosomal escape roots. Here, we report a nonendocytic approach for preferential and rapid mitochondrial delivery of molecular drugs using a designed nanocarrier. The drug-loaded nanocarrier rapidly enters into the cell via temporary membrane pore formation, releases molecular drugs into cytosol without any vesicular entrapment, and labels mitochondria within 5 min. In contrast, control nanocarrier-based delivery of the same molecule via endocytic root leads to lysosomal trafficking. This result demonstrates the advantage of the nonendocytic approach for efficient mitochondrial targeting of drugs with potential therapeutic advantages.