Deep Tumor Penetration of CRISPR-Cas System for Photothermal-Sensitized Immunotherapy via Probiotics

Since central cells are more malignant and aggressive in solid tumors, improving penetration of therapeutic agents and activating immunity in tumor centers exhibit great potential in cancer therapies. Here, polydopamine-coated Escherichia coli Nissle 1917 (EcN) bearing CRISPR-Cas9 plasmid-loaded liposomes (Lipo-P) are applied for enhanced immunotherapy in deep tumors through activation of innate and adaptive immunity simultaneously. After accumulation in the tumor center through hypoxia targeting, Lipo-P could be detached under the reduction of reactive oxygen species (ROS)-responsive linkers, lowering the thermal resistance of cancer cells via Hsp90a depletion. Owing to that, heating induced by polydopamine upon near-infrared irradiation could achieve effective tumor ablation. Furthermore, mild photothermal therapy induces immunogenic cell death, as bacterial infections in tumor tissues trigger innate immunity. This bacteria-assisted approach provides a promising photothermal-sensitized immunotherapy in deep tumors.