A natural product-derived nanozyme regulator induced chemo-ferroptosis dual therapy in remodeling of the tumor immune microenvironment of hepatocellular carcinoma

Ferroptosis, an emerging cell death mode discovered in recent decades, is characterized by lipid peroxidation during cell death, usually manifested as iron accumulation. However, the forthright delivery of iron species will cause adverse detrimental effects such as anaphylactic reactions in routine tissues. So far, studies on cellular ferroptosis by employing bio-derived nanomaterials have rarely been acquired. Herein, we reported carbon dots (CDs)-based biocompatible enzymes with negligible toxicity from a representative hepatoprotective triterpenoid natural product ursolic acid (UA) with acknowledged antitumor activity. We observed that CDs presented distinct GSH oxidase-like characteristics and then contributed ferroptosis of carcinoma cells by interfering with the GPX4-catalyzed lipid repair system. After the CDs were assembled with UA, the obtained denoted as UCDs integrated multi-model therapy into one, resulting in enhanced therapeutic efficacy, reduced adverse effects, and optimized clinical outcomes. In vivo, the UCDs hysterically inhibited tumor growth in hepatoma H22-bearing mice with inconsequential toxicity. Exceptionally, UCDs enlisted a large number of tumor-infiltrating immune cells, including T cells, NK cells, and macrophages in H22 tumor-bearing mice, consequently transforming "cold" into "hot" tumors to activate systemic anti-tumor immune responses. Meanwhile, UCDs could also awfully suppress the H22-LUC tumor growth in orthotopic xenograft mouse models. Collectively, our research commends that the drug delivery systems based on natural-products-derived CDs can function as biocompatible enzymes for antitumor treatment and may facilitate the advancement of nanotechnology-based immunotherapeutics. It is extremely anticipated that such ferroptosis-like designing in nano-catalytic medicine would be favorable for future development in cancer-therapeutic regimens.