Biomimetic “Trojan Horse” delivery of traditional Chinese medicine with immunogenic hybrid vesicles of bacterial outer membrane and tumor cell membrane for synergistic chemo-immunotherapy of liver cancers

Nowadays it is a big challenge to treat liver cancer, owing to the lack of efficient therapeutic paradigms. Currently, the first-line chemotherapy and immunotherapy often suffer from drug resistance, and severe side effects. The emerging Chinese medicine of Glycyrrhizic acid (GA) shows promise for liver cancer therapy, but often exhibits substantial toxicity and side effects. To explore efficient liver cancer treatment paradigms, herein, a "Trojan Horse" strategy is developed using biomimetic nanoplatform to deliver GA for dual chemo-immunotherapy of liver cancer. The nanoplatform (GANPs@COP) is composed of PLGA-coated GANP (GANPs@P) as the core, and hybrid vesicle (CO) of tumor cell membranes (CMVs) and bacterial outer membranes (OMVs) as the shell. In the nanoplatform, CMVs and OMVs contribute to tumor targeting and immunogenicity, respectively, while GA executes chemotherapy to locally destruct primary tumor cells. The nanoplatform synergistically ablate tumors by modulating tumor immunosuppressive microenvironment, promoting secretion of inflammatory cytokines, repolarizing macrophage M2 to M1, maturating dendritic cells, and eliciting CD8⁺ T cell infiltration, with significantly boosted therapeutic outcomes. Importantly, the nanoplatform even constructs immune memory effects for long-term tumor inhibition. This study offers a novel perspective for the combined application of traditional Chinese medicine therapy and immunotherapy of liver cancer.