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

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 (MDSCs), and enhanced T-cell infiltration, ultimately potentiating anti-tumor efficacy. Overall, this study provides an innovative strategy for targeted elimination of intra-tumoral pathogens and reversal of CRC-related immunosuppression.