4.8 Article

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

Journal

ADVANCED MATERIALS
Volume 35, Issue 14, Pages -

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.202206989

Keywords

cancer therapy; injectable hydrogel; membrane-fusogenic nanoparticles; natural killer cells; tumor surface glycan

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A core-shell membrane-fusogenic liposome (MFL) was designed to reverse the immunosuppressive effects of tumor cell surface glycans and enhance tumor elimination through the presentation of NK-activating glycans. This was achieved by fusing the MFL with tumor cell membranes, delivering sialyltransferase-inhibitor-loaded cores into the cytoplasm to downregulate immunosuppressive sialic acid, and anchoring NK-activating-glycan-modified shells onto the tumor surface. The reprogrammed tumor surface resulted in NK activation and improved tumor susceptibility to NK-cell-mediated recognition and lysis.
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.

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