A Translatable Nanoprodrug Integrates Traditional Chinese and Western Medicines for Chemo-Immunotherapy of Hepatocellular Carcinoma via Ferroptosis

Integrating traditional Chinese and Western medicine (TCWM) represents a promising therapeutic strategy for many malignant diseases, including hepatocellular carcinoma (HCC) by leveraging the complementary strengths of each therapeutic species, which, however, remains relatively unexplored to our knowledge. Herein we develop FANPs, a carrier-free nanoprodrug self-assembled from a binary prodrug based on 5-fluorouracil (5-FU) and a traditional Chinese medicine derivative, 3,19-isopropyl andrographolide (IPADE) connected via an ester link for chemo-immunotherapy of HCC. IPADE can not only induce ferroptosis and CD8+ T cells infiltration but also show cytotoxicity greater than that of the parent ADE. A breakthrough of this nanoprodrug development is a traditional core idea (5-FU) encapsulated in an emerging framework (TCWM integration) design. FANPs achieve a high tumor growth inhibition (TGI) of 89.1% in a C57BL/6J mouse model, which outperforms significantly the therapeutic efficiencies of the groups treated with either a single 5-FU (TGI: 22.2%), IPADE (53.3%) or a physically mixed dosage (61.8%). Further combination use of FANPs with a PD-1/PD-L1 small molecule inhibitor boosts adaptive immunity, which ultimately leads to a superior TGI of 97.6% in a murine HCC model. Overall, this study not only reveals ADE and its derivatives’ antitumor properties, but also develops a carrier-free nanoplatform based on the concept of integrated TCWM as a translatable technology for potential clinical treatment of HCC.