Bio-responsive Au-miR-183 inhibitor enhances immunotherapy in hepatocellular carcinoma by inducing immunogenic cell death.

ABSTRACT

The treatment of advanced hepatocellular carcinoma (HCC) is limited, and immunotherapy is the current research focus of multi-disciplinary collaborative comprehensive treatment of HCC. Herein, we constructed a bio-responsive Au-miR-183 inhibitor (Au@miR-183i) delivery system targeting liver cancer stem cells (LCSCs), and adopted the strategy of combining αPD-L1 immunotherapy. The multifunctional Au@miR-183i nanocomplexes (NCs), which self-assemble based on the tumor microenvironment, consume NADPH and H2O2, leading to redox homeostasis disturbance, ROS accumulation, regulation of the LCSC niche, and induction of stemness regression. Moreover, self-assembled Au@miR-183i NCs specifically target the delivery of miR-183i to LCSCs, triggering the immunogenic cell death (ICD) effect, promoting the maturation of dendritic cells, inducing infiltration of CD8+ T cells, and facilitating the transformation of 'cold' tumors into 'hot' tumors. More importantly, consistent with the results in vitro, Au@miR-183i NCs demonstrated effective tumor targeting and strong ICD induction in vivo, assisted in enhancing αPD-L1 immunotherapy, and activated a robust systemic anti-tumor immune response in tumor-bearing mouse models. Overall, we provide a simple and universal therapeutic strategy by constructing a multifunctional bio-responsive Au@miR-183i NCs delivery system with LCSC targeting capability. Furthermore, nanocomplex-based ICD inducers have great promise in enhancing anti-tumor immunity and the PD-1/PD-L1 blocking efficacy in HCC, which provides a theoretical basis for effectively eliminating LCSCs and achieving a high-efficiency synergistic treatment strategy for HCC.