Polysaccharide Nanodonuts for Photochemotherapy-Amplified Immunogenic Cell Death to Potentiate Systemic Antitumor Immunity Against Hepatocellular Carcinoma

Immunotherapy shows great promise in the treatment of hepatocellular carcinoma (HCC), however, the low response rate of HCC patients to immunotherapy caused by inadequately immunogenic and immunosuppressive tumor microenvironment (TME) is a huge challenge. Herein, a donut-like multifunctional polysaccharide nanoplatform (GH-PID) is constructed from doxorubicin/aldehyde hyaluronan nanoring, indocyanine green/hydroxyethyl chitosan nanocomplex, and HCC-bitargeted galactosamine-hyaluronan conjugate via a facile self-assembly process. The GH-PID nanodonuts exhibit excellent HCC-targeted ability and synergetic photochemotherapy effect with a coefficient index of about 0.44. Moreover, near infrared laser-irradiated GH-PID nanodonuts show robust therapeutic efficacy in HCC mouse models by virtue of photochemotherapy-augmented immunogenic cell death (ICD) effect. The remarkable ICD in combination with programmed death-1 antibody efficiently eradicates primary tumors and inhibits distant tumor growth and lung metastasis of HCC by maturing dendritic cells, increasing CD8⁺ T cell infiltration, suppressing the expansion and trafficking of immunosuppressive myeloid-derived suppressor cells, and ameliorating immunosuppressive TME. This study provides a facile and versatile strategy to construct polysaccharide nanodonuts integrating multifunctionality and highly efficient HCC-targeted ability, and the nanodonuts-based ICD inducer holds great promise for potentiating systemic antitumor immunity and programmed death-1/programmed death-ligand 1 blockade efficacy.