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

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 Fe 2+ -Mg 2+ 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 Fe 2+ -Mg 2+ 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 Fe 2+ -Mg 2+ 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. • Designed a Mg/Ce-MOF@MUFA-PLs nanocoupled system to block ferroptotic trigger waves through multilevel intervention. • MUFA-PLs coating enabled targeted delivery and rapid formation of ferroptosis-resistant lipid barriers. • Intracellular Fe 2+ -Mg 2+ displacement and ROS clearance reconstruct the cellular redox system. • Introduced FTWs into the bone microenvironment, offering a novel wave-dynamics framework for iron overload pathology