Metabolically engineered chimeric probiotic-cancer vesicles orchestrate anti-tumor systemic immunity.

The paradigm shift toward patient-centric precision medicine has established personalized cancer vaccines (PCVs) as a key strategy for eliciting tumor-selective immunity. However, traditional cell-based PCVs face significant translational barriers, including manufacturing complexity and safety concerns. While tumor-derived extracellular vesicles (TDEVs) offer a promising cell-free alternative that recapitulates the parental tumor's antigenic landscape, their therapeutic efficacy is frequently antagonized by intrinsic immunosuppressive cargo. Here, we report ChimeraVax, a chimeric vesicular vaccine platform engineered by covalently conjugating TDEVs with Lactobacillus acidophilus-derived membrane vesicles (LAMVs) via bio-orthogonal, copper-free click chemistry. In this hybrid assembly, the TDEVs serve as a comprehensive antigen reservoir, while the LAMVs provide potent natural adjuvanticity that bypasses TDEV-mediated immunosuppression. In vitro, ChimeraVax facilitated the synchronized delivery of tumor antigens and immunostimulatory molecules to dendritic cells, significantly enhancing antigen uptake and pro-inflammatory signaling. In a murine model of aggressive triple-negative breast cancer, subcutaneous administration of ChimeraVax coordinated both innate and adaptive immune responses, yielding robust antitumor efficacy. Notably, ChimeraVax showed strict antigen dependence, selectively suppressing matched lesions with minimal effects on mismatched tumors, highlighting its specificity and translational potential as a modular personalized cancer vaccine platform.