Mannose modified graphene oxide drug-delivery system targets cancer stem cells and tumor-associated macrophages to promote immunotherapeutic efficacy

Hepatocellular carcinoma (HCC) ranks among the most lethal tumors globally, characterized by high propensity for recurrence and metastasis. Consequently, the imperative challenge is to pioneer novel pharmaceuticals and therapeutic methodologies for efficacious liver cancer treatment. In the present study, we successfully synthesized a mannose modified Graphene Oxide-PGPML nanoparticles delivery system for remodeling the HCC tumor microenvironment though targeting cancer stem cells. These mannose modified-PGPML nanoparticles possess the capability to target canncer stem cell and M2 tumor-associated macrophages (TAMs) through specific binding to mannose receptor C Type 2 (MRC2) and macrophage mannose Receptors (MMRs). Within the acidic tumor microenvironment, the PGPML nanoparticles could inhibit proliferation, migration and reverse the epithelial-mesenchymal transition (EMT), which efficiently displayed the anti-tumor efficacy with HCC tumors in vitro and in vivo. Mechanically, the PGPML nanoparticles significantly downregulated the expression of cancer stem cell marker CD133, attenuates PD-L1 expression within the tumor microenvironment (TME), thereby reducing tumor stemness characteristics, promoting T cell activation and macrophage M2-M1 repolarization to remodel TME, augments the levels of reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-α) in tumor cells, fostering tumor cell demise. Collectively, our findings underscore that a synergistic treatment approach combining cancer stem cell-targeted therapy with immunotherapy holds promise as a potential therapeutic strategy for HCC.