Membrane‐Fusion‐Mediated Multiplex Engineering of Tumor Cell Surface Glycans for Enhanced NK Cell Therapy

Abstract Natural killer (NK) cell therapies show potential for tumor treatment but are immunologically resisted by the overexpressed immunosuppressing tumor cell surface glycans. To reverse this glycan‐mediated immunosuppression, the surface NK‐inhibitory glycan expressions need to be downregulated and NK‐activating glycan levels should be elevated synchronously with optimal efficiency. Here, a core–shell membrane‐fusogenic liposome (MFL) is designed to simultaneously achieve the physical modification of NK‐activating glycans and biological inhibition of immunosuppressing glycans on the tumor cell surface via a membrane‐fusion manner. Loaded into a tumor‐microenvironment‐triggered‐degradable thermosensitive hydrogel, MFLs could be conveniently injected and controllably released into local tumor. Through fusion with tumor cell membrane, the released MFLs could simultaneously deliver sialyltransferase‐inhibitor‐loaded core into cytoplasm, and anchor NK‐activating‐glycan‐modified shell onto tumor surface. This spatially‐differential distribution of core and shell in one cell ensures the effective inhibition of intracellular sialyltransferase to downregulate immunosuppressing sialic acid, and direct presentation of NK‐activating Lewis X trisaccharide (LeX) on tumor surface simultaneously. Consequentially, the sialic acid‐caused immunosuppression of tumor surface is reprogrammed to be LeX‐induced NK activation, resulting in sensitive susceptibility to NK‐cell‐mediated recognition and lysis for improved tumor elimination. This MFL provides a novel platform for multiplex cell engineering and personalized regulation of intercellular interactions for enhanced cancer immunotherapy.