Premium
Hypoxia‐Induced Pro‐Protein Therapy Assisted by a Self‐Catalyzed Nanozymogen
Author(s) -
Li Xudong,
Wei Yuansong,
Wu Yuchen,
Yin Lichen
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202004008
Subject(s) - hypoxia (environmental) , rnase p , glucose oxidase , chemistry , intracellular , ribonuclease , azobenzene , catalysis , protein biosynthesis , biochemistry , hyaluronic acid , biophysics , microbiology and biotechnology , oxygen , enzyme , rna , biology , organic chemistry , genetics , molecule , gene
The success of intracellular protein therapy demands efficient delivery and selective protein activity in diseased cells. Therefore, a cascaded nanozymogen consisting of a hypoxia‐activatable pro‐protein, a hypoxia‐inducing protein, and a hypoxia‐strengthened intracellular protein delivery nanovehicle was developed. RPAB, an enzymatically inactive pro‐protein of RNase, reversibly caged with hypoxia‐cleavable azobenzene, was delivered with glucose oxidase (GOx) using hypoxia‐responsive nanocomplexes (NCs) consisting of azobenzene‐cross‐linked oligoethylenimine (AOEI) and hyaluronic acid (HA). Upon NC‐mediated delivery into cancer cells, GOx catalyzed glucose decomposition and aggravated tumoral hypoxia, which drove the recovery of RPAB back to the hydrolytically active RNase and expedited the degradation of AOEI to release more protein cargoes. Thus, the catalytic reaction of the nanozymogen was self‐accelerated and self‐cycled, ultimately leading to a cooperative anti‐cancer effect between GOx‐mediated starvation therapy and RNase‐mediated pro‐apoptotic therapy.