Hypoxia‐Induced Pro‐Protein Therapy Assisted by a Self‐Catalyzed Nanozymogen

Abstract

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.

Tailoring Hyperbranched Poly(β‐amino ester) as a Robust and Universal Platform for Cytosolic Protein Delivery

“…An alternative approach involves the covalent modification of proteins with anionic species, such as carboxylic acid, [ 11 ] boronic acid, [ 12 ] or other anionic proteins, [ 5 ] peptides, [ 13 ] nucleic acids, [ 14 ] and polymers, [ 2 ] such that the modified proteins could form nanocomplexes (NCs) with cationic materials via electrostatic interactions. Although these chemically modified moieties could be removed by intracellular stimuli such as reduction, [ 15 ] reactive oxygen species (ROS), [ 12 ] enzyme, [ 16 ] hypoxia, [ 17 ] and endo/lysosomal acidity, [ 18 ] the bioactivity of the native protein is often compromised. In addition, the complicated synthetic procedures may impede the potential translation.…”

Designing Hypoxia‐Responsive Nanotheranostic Agents for Tumor Imaging and Therapy

“…As shown in Figure 10c, GOx is an enzyme that effectively catalyzes the conversion of glucose, oxygen, and water into H 2 O 2 and gluconic acid. Very recently, Yin and co‐workers [ 99 ] designed a hypoxia triggered cascade, self‐catalyzed nanozymogen, to deliver hypoxia‐strengthened RPAB (a proprotein of Rnase A reversibly caged with hypoxia‐cleavable azobenzene) and GOx. Upon the consumption of oxygen by GOx, the tumor hypoxia may be exacerbated to trigger the decomposition of AOEI to further release GOx and recover RPAB to active RNase.…”

Tumor-Selective Cascade-Amplified Dual-Prodrugs Activation for Synergistic Oxidation-Chemotherapy

“…24,25 For example, Chen and co-workers 26 amplified prodrug activation by sequentially delivering combretastatin A4 to upregulate metalloproteinase 9 (MMP9) and MMP9-activated doxorubicin (DOX) prodrug and promote activation of tumor-selective prodrug for cancer therapy. In addition, Yin and co-workers 27 reported that a pro-protein therapy was activated by self-amplified hypoxia associate enzymes. Consequently, development of an enzyme-responsive prodrug, which can simultaneously retain selectivity of enzymeresponsive for tumor targeting and amplification of the enzyme response signal for enhanced therapeutic efficiency, remains a great challenge.…”