Outer membrane vesicle-coated ferrocene nanoparticles induce dual ferroptosis for cancer immunotherapy

Fusobacterium nucleatum (Fn.) can colonize breast cancer tissue to promote tumor progression by inducing immunosuppression. Targeted therapeutic strategies against intratumoral bacteria remain unexplored and have potential in tumor immunotherapy. Here, a novel biomimetic nanoparticle (FMV@PCFPC) is developed for intratumoral immunosuppressive bacteria clearance and tumor immunogenic cell death (ICD) activation by inducing dual ferroptosis in intratumoral bacteria and tumors. A host-guest complex of hemirotaxane (mPEG-β-CD/α-CD) and polyethyleneimine-ferrocene (Fc-PEI) is constructed, designated as PCFP. PCFP is loaded with antibacterial drug cinnamaldehyde (CA) and wrapped with Fn.-secreted vesicles (FMVs) to form the system FMV@PCFPC. FMVs assist PCFPC in targeting tumors to promote ferrocene and cinnamaldehyde uptake. Fe²⁺ in ferrocene, together with glutathione (GSH) -consuming cinnamaldehyde, induces ferroptosis in intratumoral bacteria to relieve tumor immunosuppression. Similarly, PCFPC induces tumor ferroptosis to activate ICD, therefore enhancing antigen presentation and DC maturation. ICD activation works synergistically with intratumoral bacteria clearance to promote cytotoxic T lymphocytes (CTL) activation, inducing robust tumor destruction. Furthermore, killed Fn. bacterial fragments and pathogen-associated molecular patterns (PAMPs) on FMVs function as immunologic adjuvants to further boost immune response. This strategy of intratumoral bacterial clearance and tumor ICD activation relies on dual ferroptosis to effectively enhance anti-tumor immunity, showing great potential in breast cancer treatment.