Cell-penetrating Mitochondria-targeting Ligands for Universal Delivery of Small Molecules, Proteins and Nanomaterials.

Abstract

Mitochondria are key organelles that perform vital cellular functions such as cell survival and death. Targeted delivery of different types of cargos to mitochondria is a well-established strategy to study mitochondrial biology and diseases. Of various existing mitochondria-transporting vehicles, most of them suffered from poor cytosolic entry, low delivery efficiency, limited cargo types, and cumbersome preparation protocols, and none was known to be universally applicable for mitochondrial delivery of different types of cargos (small molecules, proteins and nanomaterials). Herein, we disclose two new cell-penetrating mitochondria-targeting ligands (named MitoLigand), as well as their corresponding chemoselective conjugation chemistry, that are capable of effectively tagging small- molecule drugs, native proteins and nanomaterials. Upon successful cellular delivery and rapid endosome escape, the released native cargos were found to be predominantly localized inside mitochondria. Finally, by successfully delivering doxorubicin, a well-known anticancer drug, to the mitochondria of HeLa cells, we showed the released drug possessed potent cell cytotoxicity, caused disruption of mitochondrial membrane potential and finally led to cell apoptosis. Our strategy thus paves the way for future mitochondria-targeted therapy with a variety of biologically active agents.