Camouflaging Attenuated Salmonella by Detachable Metal Polyphenol Nanoshells for Enhanced Bacteria-Based Cancer Immunotherapy

We developed Salmonella typhimurium VNP20009 camouflaged biodegradable metal polyphenol nanoshells for efficiently reducing bacterial virulence and prolonging bacterial in vivo circulation time to increase bacterial tumor enrichment. The four-layer nanoshell-encapsulated VNP20009 (M₄@V) ensured the safety of treatment by effectively inhibiting bacterial proliferation and significantly reducing the toxicity in vivo. Moreover, the nanoshells significantly enhanced the biocompatibility of VNP20009 to protect it from phagocytosis, resulting in a 4-fold in vivo circulation time and a 1.97-fold increase in peak accumulation at the tumor sites. After the M₄@V colonized in the tumor microenvironment, physiologically relevant levels of ascorbic acid (AA) triggered the degradation of the nanoshells to restore the proliferation of VNP20009 at the tumor sites. Within 4T1 tumor-bearing mouse models, the AA+M4@V showed remarkable efficacy in suppressing both primary and metastatic tumors and was accompanied by a highly specific immune response.