An "All-in-one" Immunomodulator-Engineered Clinical Translatable Immunotherapy of Advanced Hepatocellular Carcinoma.

Clinical treatment of advanced hepatocellular carcinoma (HCC) remains a significant challenge. The use of RRx-001 with the function of downregulating the expression of innate immune checkpoint molecule CD47 provides a powerful means for treating advanced HCC containing a substantial proportion of immunosuppressive macrophages. We reported herein engineering of a previously optimized DOX-delivery nanoplatform based on sodium alginate to further co-deliver RRx-001 (BEA-D@R) for efficient immunotherapy of advanced HCC. The breakthrough of this technique is the disclosure of the "all-in-one" immunotherapeutic functionalities of RRx-001 for potent HCC immunotherapy. Besides the previously demonstrated functions of downregulating CD47 expression and reactive nitrogen species (RNS) generation, another key function of RRx-001 for downregulating the expression of the adaptive immune checkpoint molecule PDL1 has been uncovered for the first time. Combined with the ROS generation and an upregulated "eat me" signal level of DOX, BEA-D@R collectively increased RNS generation, enhanced T cell infiltration, and maximized macrophage phagocytosis, leading to an average of 40% tumor elimination in a mice model bearing an initial tumor of approximately 300 mm 3 that mimics advanced HCC. Overall, this study uncovered the "all-in-one" immunotherapeutic functionalities of a clinical translatable nanoplatform for enhanced immunotherapy of advanced HCC. This article is protected by copyright. All rights reserved.