Fusobacterium nucleatum-targeted polymeric micelles disrupting biofilm-immune crosstalk for precision colorectal cancer immunotherapy

作者：T.-C. Wu, Fuping Zhang, Hongyu Liu, Feihe Ma, Yunjian Yu, Daxi Sun, Juan Ren, Wentao Wang, Mahmoud Elsabahy, Hui Gao · 发表于：Journal of Controlled Release · 年份：2025 · DOI：10.1016/j.jconrel.2025.114400 · 被引用次数：3 · 研究领域：Nanoplatforms for cancer theranostics、Cancer Research and Treatments、Immune cells in cancer

Targeted eradication of Fusobacterium nucleatum (Fn)-dominated biofilms within the colorectal cancer (CRC) microenvironment emerges as a promising strategy to overcome bacterial resistance and reverse immunosuppression. Herein, pH-responsive biofilm-targeting polymeric micelles (ERPNPs) are developed to disrupt biofilm-immune crosstalk for CRC immunotherapy. The ERPNPs are constructed by co-loading rifampicin (RIF) and epigallocatechin gallate (EGCG, a biofilm-dispersing agent) into self-assembled polymeric micelles incorporating a FadA-targeting peptide (Pep) for specific biofilm recognition. At physiological pH, the polyethylene glycol shell facilitates efficient tumor accumulation of ERPNPs, while in the acidic tumor microenvironment, protonation of poly(β-amino ester) (PAE) segments trigger conformational switching, exposing the Pep for specific recognition of Fn biofilms through FadA-Pep ligand-receptor interactions, accompanied by pH-responsive release of RIF and EGCG. In vitro experiments demonstrate that ERPNPs can efficiently scavenge Fn biofilms via pH-dependent and FadA-Pep-mediated targeted adhesion. In vivo studies further reveal their excellent biocompatibility, robust biofilm-scavenging, and anti-tumor activities. Mechanistically, ERPNPs eradicate Fn biofilms and reduce immunosuppressive polyamine metabolites, thereby eliciting systemic immune responses characterized by M1 macrophage polarization, suppressed recruitment of myeloid-derived suppressor cells (MDSC...