Lyotropic liquid crystalline nanoparticles with bicontinuous cubic internal nanostructure, known as cubosomes, have been proposed as nanocarriers in various medical applications. However, as these nanoparticles show a certain degree of cytotoxicity, particularly against erythrocytes, their application in systemic administrations is limited to date. Intending to produce a more biocompatible formulation, we prepared cubosomes for the first time stabilized with a biodegradable polyphosphoester-analog of the commonly used Pluronic F127. The ABA-triblock copolymer poly(methyl ethylene phosphate)-block-poly(propylene oxide)-block-poly(methyl ethylene phosphate) (PMEP-b-PPO-b-PMEP) was prepared by organocatalyzed ring-opening polymerization of MEP. The cytotoxic features of the resulting formulation were investigated against two different cell lines (HEK-293 and HUVEC) and human red blood cells. The response of the complement system was also evaluated. Results proved the poly(phosphoester)-based formulation was significantly less toxic than that prepared using Pluronic F127 with respect to all the tested cell lines and, more importantly, hemolysis assay and complement system activation tests demonstrated its very high hemocompatibility. The potentially biodegradable poly(phosphoester)-based cubosomes represent a new and versatile platform for preparation of functional and smart nanocarriers. (C) 2020 Elsevier Inc. All rights reserved.