Reconstituted phospholipid membrane-coated Fe²⁺-Mg²⁺ displacement nanoparticles block ferroptotic trigger waves.

Abstract

Ferroptotic trigger waves (FTWs) mediate the long-distance propagation of transient cell-death signals across tissues, resulting in spatially correlated, large-scale cellular dysfunction and programmed demise. Blocking of FTWs represents a promising therapeutic strategy for iron accumulation-related pathologies. Based on spatial characteristics of FTWs, this study developed a nanocoupled system (Mg/Ce-MOF@MUFA-PLs) integrating "intracellular-membrane-cell population" multi-physical level to block FTWs, aiming to efficiently block FTWs through precise cellular targeting, resistance of target cell membrane lipid peroxidation, and intracellular Fe²⁺-Mg²⁺ displacement. This study employed coordination chemistry synthesis combined with short-range electrostatic interactions to prepare Mg/Ce-MOF with toxic oxygen radical scavenging enzyme activity and Fe²⁺-Mg²⁺ displacement capability; subsequently, the composite nanoparticles were coated with monounsaturated fatty acid phospholipids (MUFA-PLs) to endow them with capabilities of precise targeting and cell membranes MUFA-PLs ratio enhancing. In vitro and in vivo experiments confirmed that Mg/Ce-MOF@MUFA-PLs achieving near 100% equimolar Fe²⁺-Mg²⁺ displacement within 4 h, significantly increasing MUFA-PLs of target cell membrane and enabling efficient Mg/Ce-MOF delivery, over threefold improvement in ferroptosis resistance and redox systems compared to controls, and efficient bone mass enhancement with rapid defect healing in ovariectomized (OVX) mice/rats over 8 weeks. This FTWs-blocking strategy provides a paradigm for treating iron accumulation-related diseases.