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

• Published in: Advanced materials (Weinheim) Vol. 35; no. 14; pp. e2206989 - n/a
• Main Authors: Zheng, Chunxiong, Zhong, Qingguo, Song, Wantong, Yi, Ke, Kong, Huimin, Wang, Haixia, Tao, Yu, Li, Mingqiang, Chen, Xuesi
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.04.2023
• Subjects: cancer therapy; Cell Membrane - metabolism; Cell membranes; Cell- and Tissue-Based Therapy; Cytoplasm; Glycan; Humans; Hydrogels; Immunosuppression; injectable hydrogel; Materials science; membrane‐fusogenic nanoparticles; Multiplexing; N-Acetylneuraminic Acid; natural killer cells; Neoplasms - therapy; Oligosaccharides; Polysaccharides; Sialyltransferases; Tumor Microenvironment; tumor surface glycan; Tumors; membrane-fusogenic nanoparticles; cancer therapy; injectable hydrogel; natural killer cells; tumor surface glycan
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.202206989

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. A core–shell membrane‐fusogenic liposome is designed to fuse with tumor cell membrane to deliver sialyltransferase inhibitor‐loaded core into cytoplasm and anchor natural killer (NK)‐activating glycan‐modified shell onto surface synchronously. This membrane‐fusion‐mediated delivery approach reprograms the sialic acid‐caused immunosuppression of tumor surface into a Lewis X trisaccharide‐based NK‐activating type, sufficiently reactivating the NK recognition and lysis for enhanced antitumor therapy.