Small Methods, 29 November, 2022, DOI：https://doi.org/10.1002/smtd.202201086

Ferritin Nanocaged Doxorubicin Potentiates Chemo-Immunotherapy against Hepatocellular Carcinoma via Immunogenic Cell Death

Yang Chen, Linyuan Zeng, Hongzhang Zhu, Qifei Wu, Rong Liu, Qian Liang, Bin Chen, Haitao Dai, Keyu Tang, Changli Liao, Yonghui Huang, Xiyun Yan, Kelong Fan, Jin-Zhi Du, Run Lin, Jun Wang

Abstract

Although immunotherapy of hepatocellular carcinoma using immune checkpoint inhibitors has achieved certain success, only a subset of patients benefits from this therapeutic strategy. The combination of immunostimulatory chemotherapeutics represents a promising strategy to enhance the effectiveness of immunotherapy. However, it is hampered by the poor delivery of conventional chemotherapeutics. Here, it is shown that H-ferritin nanocages loaded with doxorubicin (DOX@HFn) show potent chemo-immunotherapy in hepatocellular carcinoma tumor models. DOX@HFn is constructed with uniform size, high stability, favorable drug loading, and intracellular acidity-driven drug release. The receptor-mediated targeting of DOX@HFn to liver cancer cells promote cellular uptake and tumor penetration in vitro and in vivo. DOX@HFn triggers immunogenic cell death to tumor cells and promotes the subsequent activation and maturation of dendritic cells. In vivo studies in H22 subcutaneous hepatoma demonstrate that DOX@HFn significantly inhibits the tumor growth with >30% tumors completely eliminated, while alleviating the systemic toxicity of free DOX. DOX@HFn also exhibits robust antitumor immune response and tumoricidal effect in a more aggressive Hepa1-6 orthotopic liver tumor model, which is confirmed by the in situ magnetic resonance imaging and transcriptome sequencing. This study provides a facile and robust strategy to improve therapeutic efficacy of liver cancer.

Article link：https://onlinelibrary.wiley.com/doi/10.1002/smtd.202201086