Coordination polysaccharide nanomissiles with size/charge dual-transformability and immunomicroenvironment-reeducating activity potentiate PD-1 blockade in hepatocellular carcinoma

Abstract

PD-1 blockade therapy holds great potential for curing hepatocellular carcinoma (HCC), but its efficacy is severely restrained by inefficient CD8+ T cells and abundant immunosuppressive myeloid-derived suppressor cells (MDSCs) in tumors. Moreover, the solid feature of HCC limits drugs’ penetration depth. Herein, cisplatin/indocyanine green (ICG)-coloaded polysaccharide-based nanomissiles (CIC-Gal) with galactose-mediated tumor targeting ability and tumor microenvironment (TME)-responsive size/charge dual-transformability are constructed by coordination-driven self-assembly. The nanoparticles can efficiently accumulate in tumors and exert antitumor effects on HCC via combinational chemotherapy/phototherapy. Importantly, CIC-Gal nanoparticles may protect cisplatin from glutathione-mediated detoxification by depleting glutathione. Photodynamic therapy rather than photothermal therapy plays a predominant role in ICG-mediated phototherapy. Furthermore, CIC-Gal nanoparticles can induce prominent immunogenic cell death (ICD), promote dendritic cells maturation, and activate robust systemic antitumor immunity in combination with αPD-1, which efficiently eradicates primary tumors, inhibits distant tumor growth and lung metastasis, and prolongs survival of tumor-bearing mice by promoting CD8+ T cell infiltration in tumors, suppressing the expansion and trafficking of MDSCs, and reshaping immunostimulatory TME. Collectively, this study provides a drug-based coordination-driven polysaccharide nanomissile construction approach, and the CIC-Gal nanoparticles display a strong immunomicroenvironment-reeducating ability for potentiating HCC immunotherapy.