In situ Polymerization via Bioorthogonal Condensation in Mitochondria Controls Cell Fate

Abstract

Living organisms are composed of natural and functional nanomaterials including DNA, protein, and lipid membrane. Nanomaterials have a crucial role, interact with cell components and sometimes control cell fate. In biomedical applications, artificial nanomaterials have been designed to mimic biological materials in living systems. However, the main challenge of the nanomaterials is a low delivery efficiency due to poor tissue distribution and immune response under physiological barriers. Thus, in situ self-assembly or polymerization have been studied to construct nanomaterials in living systems. Bioorthogonal condensation is one of the strategies for in situ nanomaterial construction inside a complex biological environment. These reactions are fast, highly selective, and can be regulated by physiological stimuli such as pH, reductive environment, and enzyme activities. Herein, we presented a smart in situ polymerization system via bioorthogonal condensation between 2-cyanobenzothiazole(CBT) and Cysteine(Cys). We hypothesized that, while monomers in cytosol generally form dimers, the highly accumulated monomers within specific organelle can undergo polycondensation and form polymers in a concentration-dependent manner. In this work, we proved in situ polymerization induced by mitochondrial localization constructs nanomaterials in cells and this intra-mitochondrial polymerization controls cellular fate. Therefore, we expect in situ polymerization system would be widely applied in biomedical applications including cancer treatment.