Surface Engineering of Natural Killer Cells with CD44‐targeting Ligands for Augmented Cancer Immunotherapy

Abstract Adoptive immunotherapy utilizing natural killer (NK) cells has demonstrated remarkable efficacy in treating hematologic malignancies. However, its clinical intervention for solid tumors is hindered by the limited expression of tumor‐specific antigens. Herein, lipid‐PEG conjugated hyaluronic acid (HA) materials (HA‐PEG‐Lipid) for the simple ex‐vivo surface coating of NK cells is developed for 1) lipid‐mediated cellular membrane anchoring via hydrophobic interaction and thereby 2) sufficient presentation of the CD44 ligand (i.e., HA) onto NK cells for cancer targeting, without the need for genetic manipulation. Membrane‐engineered NK cells can selectively recognize CD44‐overexpressing cancer cells through HA‐CD44 affinity and subsequently induce in situ activation of NK cells for cancer elimination. Therefore, the surface‐engineered NK cells using HA‐PEG‐Lipid (HANK cells) establish an immune synapse with CD44‐overexpressing MIA PaCa‐2 pancreatic cancer cells, triggering the “recognition‐activation” mechanism, and ultimately eliminating cancer cells. Moreover, in mouse xenograft tumor models, administrated HANK cells demonstrate significant infiltration into solid tumors, resulting in tumor apoptosis/necrosis and effective suppression of tumor progression and metastasis, as compared to NK cells and gemcitabine. Taken together, the HA‐PEG‐Lipid biomaterials expedite the treatment of solid tumors by facilitating a sequential recognition‐activation mechanism of surface‐engineered HANK cells, suggesting a promising approach for NK cell‐mediated immunotherapy.