Micro‐to‐Nano Oncolytic Microbial System Shifts from Tumor Killing to Tumor Draining Lymph Nodes Remolding for Enhanced Immunotherapy

Abstract Because the tumor‐draining lymph nodes (TDLNs) microenvironment is commonly immunosuppressive, oncolytic microbe‐induced tumor antigens aren't sufficiently cross‐primed tumor specific T cells through antigen‐presenting cells (e.g., dendritic cells (DCs)) in TDLNs. Herein, this work develops the micro‐to‐nano oncolytic microbial therapeutics based on pyranose oxidase (P 2 O) overexpressed Escherichia coli (EcP) which are simultaneously encapsulated by PEGylated mannose and low‐concentrated photosensitizer nanoparticles (NPs). Following administration, P 2 O from this system generates toxic hydrogen peroxide for tumor regression and leads to the release of tumor antigens. The “microscale” EcP is triggered, following exposure to the laser irradiation, to secrete the “nanoscale” bacterial outer membrane vesicles (OMVs). The enhanced TDLNs delivery via OMVs significantly regulates the TDLNs immunomicroenvironment, promoting the maturation of DCs to potentiate tumor antigen‐specific T cells immune response. The micro‐to‐nano oncolytic microbe is leveraged to exert tumor killing and remold TDLNs for initiating potent activation of DCs, providing promising strategies to facilitate microbial cancer vaccination.