Remotely Controllable Supramolecular Nanomedicine for Drug‐Resistant Colorectal Cancer Therapy Caused by <i>Fusobacterium nucleatum</i>

Abstract

Fusobacterium nucleatum (Fn) existing in the community of colorectal cancer (CRC) promotes CRC progression and causes chemotherapy resistance. Despite great efforts that have been made to overcome Fn-induced chemotherapy resistance by co-delivering antibacterial agents and chemotherapeutic drugs, increasing the drug-loading capacity and enabling controlled release of drugs remain challenging. In this study, a novel supramolecular upconversion nanoparticle (SUNP) is constructed by incorporating a positively charged polymer (PAMAM-LA-CD) with Fn inhibition capacity, a negatively charged platinum (IV) oxaliplatin prodrug (OXA-COOH), upconversion nanoparticle (UCNPs) and polyethylene glycol-azobenzene (PEG-Azo) to enhance drug-loading and enable on-demand drug release for drug-resistant CRC treatment. SUNPs exhibit high drug-loading capacity (30.8%) and good structural stability under normal physiological conditions, while disassembled upon exogenous NIR excitation and endogenous azo reductase in the CRC microenvironment to trigger drug release. In vitro and in vivo studies demonstrate that SUNPs presented good biocompatibility and robust performance to overcome chemoresistance, thereby significantly inhibiting Fn-infected cancer cell proliferation. This study leverages multiple dynamic chemical designs to integrate both advantages of drug loading and release in a single system, which provides a promising candidate for precision therapy of bacterial-related drug-resistant cancers.