Metal-Free Peroxidase-Mimetic Nanocatalysts for Chemodynamic Vascular-Disrupting Cancer Therapy

Metal ion-facilitated chemodynamic therapy (CDT) is an emerging method for treating cancer. However, its potential is hindered by its low catalytic performance in weakly acidic tumor microenvironments (TMEs) and the severe toxicity of free metal ions. We introduce a new approach to tumor therapy, chemodynamic vascular disruption (CVD), using metal-free, peroxidase (POD)-mimetic multihydroxylated [70] fullerene (MHF) nanocatalysts. Our research shows that MHF contains C···O active sites, as demonstrated by density functional theory (DFT) calculations, and converts H O into •OH across a pH range of 6.0-10.0. The generation of •OH and the dismantling of tumor blood vessels are observed in real-time using mouse dorsal skin-fold chamber (DSFC) models. Applying proteomics, we discover that the CVD mechanism involves the nanocatalytic MHF enhancing H O decomposition in the TME, producing •OH. This damages tumor vascular endothelial junction proteins, causing vascular leakage and subsequently cutting off the vascular supply to the tumor cells. This method deviates from the traditional CDT that targets tumor cells. Instead, our proficient MHF nanocatalysts aim to directly disrupt the tumor vasculature, enhancing anti-tumor efficiency without triggering harmful toxicity. The proposed CVD therapeutic strategy enhances the application of gentle carbon nanocatalysts in cancer therapy, offering new perspectives on nanocatalytic medicine. This article is protected by copyright. All rights reserved.