The development of hybrid nanomaterials mimicking antifreeze proteins that can modulate/inhibit the growth of ice crystals for cell/tissue cryopreservation has attracted increasing interests. Herein, we describe the first utilization of zirconium (Zr)-based metal-organic framework (MOF) nanoparticles (NPs) with well-defined surface chemistries for the cryopreservation of red blood cells (RBCs) without the need of any (toxic) organic solvents. Distinguishing features of this cryoprotective approach include the exceptional water stability, low hemolytic activity, and the long periodic arrangement of organic linkers on the surface of MOF NPs, which provide a precise spacing of hydrogen donors to recognize and match the ice crystal planes. Five kinds of Zr-based MOF NPs, with different pore size, surface chemistry, and framework topologies, were used for the cryoprotection of RBCs. A "splat" assay confirmed that MOF NPs not only exhibited ice recrystallization inhibition activities but also acted as a "catalyst" to accelerate the melting of ice crystals. The human RBC cryopreservation tests displayed RBC recoveries of up to ∼40%, which is higher than that obtained via commonly used hydroxyethyl starch polymers. This cryopreservation approach will inspire the design and utilization of MOF-derived nanoarchitectures for the effective cryopreservation of various cell types as well as tissue samples.