Mitochondria-Targeted\nIcaritin Nanoparticles Induce\nImmunogenic Cell Death in Hepatocellular Carcinoma

Hepatocellular\ncarcinoma (HCC) is a highly malignant tumor that\nis resistant to chemotherapy and immunotherapy. Icaritin (ICT), a\ntraditional Chinese medicine, has been reported as an immunoregulatory\nagent for treating advanced unresectable HCC. ICT induces mitophagy\nto cause immunogenic cell death (ICD); however, the poor bioavailability\nof ICT limits its therapeutic efficacy and clinical use. Therefore,\nthis study aimed to assess the effect of using the poly(2-(<i>N</i>-oxide-<i>N</i>,<i>N</i>-diethylamino)\nethyl methacrylate)-<i>b</i>-poly(ε-caprolactone)\ncopolymer (OPDEA-PCL) to encapsulate ICT into nanoparticles (ICT NPs).\nOPDEA-PCL/ICT NPs colocalized with the mitochondria, promoting the\nICD induction effect of ICT in mouse HCC H22 cells. In the H22 subcutaneous\ntumor model, intravenously injected OPDEA-PCL/ICT NPs quickly accumulated\nin the tumor and efficiently activated systemic anticancer immunogenicity\nthrough their effects on mitophagy. The resulting tumor suppression\nrate was 60%, which was significantly higher than that of free ICT\nand poly(ethylene glycol) (PEG)-PCL/ICT NPs. Furthermore, mouse survival\nwas also prolonged by nearly 2-fold with OPDEA-PCL/ICT NPs compared\nwith PBS. In summary, this approach provides valuable insights into\nimproving the immunotherapeutic efficacy of ICT for HCC.