Mitochondria targeted composite enzyme nanogels for synergistic starvation and photodynamic therapy

Mitochondria, as the energy factory of cells, often maintain a high redox state, and play an important role in cell growth, development and apoptosis. Therefore, the destruction of mitochondrial redox homeostasis has now become an important direction for cancer treatment. Here, we design a mitochondrial targeting composite enzyme nanogel bioreactor with a circulating supply of O-2 and H2O2, which is composed of mitochondrial target triphenylphosphine (TPP), natural enzymes glucose oxidase (GOX) and catalase (CAT), and protoporphyrin IX (PpIX). The nanogel can effectively increase the stability of the natural enzymes, and its size of about 65 nm makes them close in space, which greatly improves their cascade catalytic efficiency and safety. Under the action of target TPP, the system can accurately target the mitochondria of breast cancer 4T1 cells, catalyze intracellular glucose to generate H2O2 through GOX, and H2O2 is further used as a catalytic substrate for CAT to generate O-2. This O-2 can not only further improve the catalytic efficiency of GOX, but also provide raw materials for the production of ROS in PDT, which can effectively destroy the mitochondria of cancer cells, thereby causing tumor cell apoptosis. Compared with GOX alone, thanks to the close spatial position of the composite enzymes, the composite enzyme nanogel can quickly consume the highly oxidative H2O2 produced by GOX, thereby showing better safety to normal cells. In addition, the composite enzyme group under light showed excellent antitumor effects by combining starvation therapy and PDT under adequate oxygen supply in animal experiments. In general, this composite enzyme nanogel system with good stability, high safety and excellent cascade catalytic efficiency opens a new way for the development of safe and efficient cancer therapeutics.

Automated summary

The designed composite enzyme nanogel system can target cancer cell mitochondria, disrupt the redox homeostasis of mitochondria through catalysis, induce tumor cell apoptosis, and showed good anti-tumor effects in animal experiments.