Microglia membrane biomimetic platinum-based MOF-loaded quercetin nanodrug delivery system for the treatment of Alzheimer's disease

Abstract

The aberrant deposition of β-amyloid (Aβ) is a central pathological hallmark of Alzheimer’s disease (AD), triggering oxidative stress, metal ion dyshomeostasis, and excessive microglial activation in a self-perpetuating pathological cascade. To address these interconnected processes, a platinum-based metal–organic framework (Pt-MOF) with intrinsic antioxidant enzyme–mimetic activity was constructed and loaded with quercetin (Qu) to regulate microglial dysfunction. To enhance blood–brain barrier (BBB) penetration and inflammation-targeting capability, Pt-MOF/Qu was further camouflaged with microglial cell membranes (BV2), yielding Pt-MOF/Qu/BV2 nanoparticles. In vitro studies demonstrated that Pt-MOF/Qu/BV2 efficiently scavenged reactive oxygen species and effectively chelated Cu²⁺ ions via surface functional groups, thereby inhibiting Aβ aggregation and promoting the disassembly of preformed Aβ aggregates. In addition, Pt-MOF enabled efficient loading and controlled release of Qu, which significantly restored mitochondrial membrane potential and alleviated microglial over-activation. The BV2 membrane coating markedly improved the biocompatibility and BBB translocation efficiency of the nanoplatform. Furthermore, in an AD Caenorhabditis elegans model, Pt-MOF/Qu/BV2 significantly reduced Aβ plaque accumulation in the head region and improved locomotor and cognitive performance. Overall, this biomimetic multifunctional MOF-based nanoplatform represents a promising multi-target therapeutic strategy for AD.