Multifunctional Artificial Peroxisome Basing on Lactate Oxidase as a Self-Cascade Enhancing Active Oxygen Amplifier for Tumor Therapy.

Abstract

The intricacy, diversity, and heterogeneity of cancers make research focus on developing multimodal synergistic therapy strategies. Herein, an oxygen (O₂) self-feeding peroxisomal lactate oxidase (LOX)-based LOX-Ce6-Mn (LCM) was synthesized using a biomineralization approach, which was used for cascade chemodynamic therapy (CDT)/photodynamic therapy (PDT) combination therapies through dual depletion of lactate (Lac) and reactive oxygen species (ROS) generation. After endocytosis into tumor cells, the endogenous hydrogen peroxide (H₂O₂) can be converted to O₂ by the catalase-like (CAT) activity of LCM, which can facilitate the catalytic reaction of LOX to consume more Lac and alleviate tumor hypoxia to enhance the generation of singlet oxygen (¹O₂) upon light irradiation. In addition, the H₂O₂ produced by LOX catalysis and oxidase-like (OXD) activity of LCM can be catalyzed into highly toxic hydroxyl radicals (^•OH) via the Fenton-like reaction, enhancing oxidative damage to tumor cells. Both in vitro and in vivo experiments confirmed that LCM significantly promoted ROS accumulation and effectively inhibited tumor growth by inducing tumor cell autophagy under the combined effect of Lac depletion and CDT with PDT. Therefore, integrally designed LCM for reprogramming metabolism and the tumor microenvironment offers a promising multimodal strategy for tumor treatments.