Enzyme-Instructed Activation of Pro-protein Therapeutics (PPT) In Vivo

The selective and temporal control of protein activity in living cells provides a powerful tool to manipulate cellular function and to develop Pro-protein Therapeutics (PPT) for targeted therapy. Herein, we report a facile yet general chemical approach to design PPT by modulating protein activity in response to endogenous enzyme of disease cells, and its potential for targeted cancer therapy. We demonstrate that the chemical modification of protein with QPN, a ligand that could be reduced by tumor cell-specific NAD(P)H dehydrogenase [quinone] 1 (NQO1), is reversible in the presence of NQO1. Importantly, the QPN-modified cytochrome c (Cyt C-QPN) and ribonuclease A (RNase A-QPN) show NQO1-regulated protein activity in a highly selective manner. Furthermore, the intracellular delivery of RNase A-QPN using a novel type of lipid-based nanoparticles, and subsequent protein activation by cellular NQO1 selectively prohibit cancer cells growth in vitro and effectively suppress tumor growth in vivo. Our approach ex...