Dual Targeting Biomimetic Nanoplatform Eradicates Oncogenic Bacteria While Reinvigorating Anti-Tumor Immunity in Breast Cancer

Mounting evidence reveals that intratumoral microbiota, particularly <i>Fusobacterium nucleatum</i> <i>(Fn)</i>, promote immunosuppression in the tumor microenvironment. We discovered that celastrol (CLT) displays concurrent cytotoxicity against triple-negative breast cancer (TNBC) cells and bactericidal effects against <i>Fn</i>. To exploit this unique dual-functionality, we developed a biomimetic system (CiTB) using hybrid membranes from engineered T cells and <i>Fn</i> to wrap CLT-loaded PLGA nanoparticles. This design utilizes overexpressed PD-1 on the T cell membrane and Fap2 proteins on the <i>Fn</i> membrane to target PD-L1 and Gal-GalNAc residues overexpressed on tumor cell surfaces, respectively. Importantly, this biomimetic system reprograms the tumor microenvironment through four synergistic effects: (1) directly clearing <i>Fn</i> to break bacteria-induced immunosuppression, (2) immune reactivation via PD-1 membrane mediated immune checkpoint blockade, (3) enhanced synergistic immunity characterized by NK cells and T cell infiltration, and (4) in-situ vaccination through combined bacterial component adjuvanticity and tumor antigen release. In <i>Fn</i>-colonized TNBC models, CiTB exhibited superior tumor accumulation and suppression as well as significant median survival length extension (from 23 to 44.5 days). CiTB also exhibited excellent biosafety without gut microbiome disruption. Thus, this study provides both a new nonantibiotic option for treating intratumor bacteria and a new biomimetic hybrid membrane technique for tumor targeting.