Biomimetic red blood cell membrane-coated cerium metal-organic framework for multi-target synergistic therapy of Alzheimer's disease.

Pathological events in Alzheimer's disease (AD) typically involve β-amyloid (Aβ) plaque deposition, metal ion dysregulation, oxidative stress elevation, and chronic neuroinflammation, making single-target therapies unsatisfactory. Here, we first report a biomimetic nanoplatform based on red blood cell membrane-coated cerium metal-organic frameworks (Ce-MOF-RBC) that enables multi-target synergistic intervention against AD. The Ce-MOF core exhibits potent antioxidant activity, efficiently scavenging reactive oxygen species (ROS) and restoring mitochondrial membrane potential, while its carboxylate ligands chelate Cu2 + with high efficiency (49.26 %) to inhibit Cu2+-induced Aβ fibrillation and disassemble preformed fibrils. Ce-MOF-RBC further modulates microglial phenotype, enhancing Aβ phagocytosis and reducing neuroinflammation. Importantly, RBC membrane functionalization markedly improves biological performance by prolonging systemic circulation, enhancing blood-brain barrier (BBB) penetration, and leveraging its intrinsic affinity for Aβ peptides to enrich Aβ. In vivo fluorescence imaging and brain cryosections showed that Ce-MOF-RBC achieved robust accumulation in the cortex and hippocampus, with brain fluorescence intensities 27.33-fold higher than free DiD. In the C. elegans AD model, Ce-MOF-RBC reduced Aβ plaque fluorescence by 32.54 %, lowered ROS levels by 45.72 %, improved chemotaxis performance (chemotaxis index increased from 34.24 % to 68.34 %), and delayed paralysis onset from 10 h to 15 h, demonstrating significant rescue of cognitive and motor deficits. In summary, these findings highlight the first demonstration of a small-sized, biomimetic Ce-MOF-RBC nanoplatform that integrates antioxidant, metal-chelating, anti-aggregation, and immunomodulatory functions, offering a promising strategy for comprehensive AD therapy.