An Anaerobic Biomimetic Metal-Free AIE Polymersome Nanozyme as NADH Oxidase Mimic for Photocatalytic Tumor Suppression by Impairing Cancer Cell Energy Metabolism under Hypoxia

The intracellular balance between nicotinamide adenine dinucleotide and its reduced form (NAD⁺/NADH) is essential for cell metabolism. The NAD⁺/NADH redox imbalance strategy using NADH-oxidase-mimic nanozymes has emerged as an attractive antitumor strategy. Here, we develop a photocatalytic metal-free nanozyme that is a polymer vesicle (polymersome) self-assembled from PEG-block-poly(amino acid) functionalized by photocatalytic moieties with aggregation-induced emission (AIE). To enhance biocompatibility and tumor-targetability, the vesicle is coated with a folate-modified red-blood-cell membrane (FA-RBC) to get biomimetic AIE polymersome nanozyme (BV). Unlike conventional photocatalysts, BV can achieve the cyclical photocatalytic process for NADH-NAD⁺ conversion without O₂ or additional electron acceptors. A new mechanism is proposed in which adjacent excited triplet molecules in the AIE assembly play the role of electron acceptors for complete NADH-NAD⁺ conversion and catalyst turnover. This O₂-independent photocatalysis is appealing in anticancer treatment since the tumor has a hypoxic microenvironment. In vitro and in vivo investigations demonstrate BV induces a severe NAD⁺/NADH imbalance under hypoxia to lead to inhibition of oxidative phosphorylation and glycolysis, which triggers the energy crisis in 4T1 cancer cells and in the 4T1 tumor of a subcutaneous xenograft model. This work presents a novel approach of cancer therapy through the photocatalytic impairment of tumor energy metabolism by metal-free nanozyme.