A Dynamic Membrane‐Active Glycopeptide for Enhanced Protection of Human Red Blood Cells against Freeze‐Stress

Abstract Intracellular delivery of freezing‐tolerant trehalose is crucial for cryopreservation of red blood cells (RBCs) and previous strategies based on membrane‐disruptive activity usually generate severe hemolysis. Herein, a dynamic membrane‐active glycopeptide is developed by grafting with 25% maltotriose and 50% p ‐benzyl alcohol for the first time to effectively facilitate entry of membrane‐impermeable trehalose in human RBCs with low hemolysis. Results of the mechanism acting on cell membranes suggest that reversible adsorption of such benzyl alcohol‐grafted glycopeptide on cell surfaces upon weak perturbation with phospholipids and dynamic transition toward membrane stabilization are essential for keeping cellular biofunctions. Furthermore, the functionalized glycopeptide is indicative of typical α ‐helical/ β ‐sheet structure‐driven regulations of ice crystals during freeze−thaw, thereby strongly promoting efficient cryopreservation. Such all‐in‐one glycopeptide enables achieving both high cell recovery post‐thaw >85% and exceptional cryosurvival >95% in direct freezing protocols. The rationally designed benzyl alcohol‐modified glycopeptide permits the development of a competent platform with high generality for protection of blood cells against freeze‐stress.