Synergistic effects of IL-3 release and Mn ²⁺-doped Prussian blue nanoparticles camouflaged with MES23.5 cell membranes on Alzheimer’s disease therapy

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with prolonged latency during the prodromal stage. However, current clinical approaches to pharmacological interventions for AD remain challenge. An effective treatment strategy is to eliminate protein aggregates and prevent their regeneration. In this study, interleukin (IL)-3-loaded porous manganese (Mn²⁺)-doped Prussian blue (PB) nanoparticles (NPs) were coated with dopaminergic MES23.5 neuronal cell membranes (PBMn-IL3@CM) and then used to combat AD progression. The PBMn-IL3@CM NPs possessed a high targeting efficiency, being able to traverse the blood-brain barrier and specifically affect the brain to reduce oxidative stress. The Mn²⁺-doped PB NPs effectively scavenged reactive oxygen radicals produced by microglia, inducing the pro-inflammatory M1 microglia. In addition, the released IL-3 activated microglia, causing the polarization of the M1 phenotype to the anti-inflammatory M2 phenotype <i>in vitro</i> and <i>in vivo</i>. The transition reduced phosphorylated tau accumulation, mediated neurotoxicity, and eliminated tau aggregates, which reversed cognitive impairment in AD mice. The PBMn-IL3@CM NPs showed excellent biocompatibility without significant adverse effects; consequently, they represent a promising AD treatment.