Engineered urinary-derived extracellular vesicles loaded nanoenzymes as Trojan horses to regulate the inflammatory microenvironment for treatment of Alzheimer's disease.

• Engineered exosomes can scavenge a variety of toxic reactive oxygen species using the activity of multiple nanozymes. • Engineered exosomes can target the brain in two ways: actively with targeted peptides and passively with photothermal action. • Engineered exosomes reduce microglia activation and mitochondrial damage. Alzheimer's disease (AD) is one of the leading causes of dementia. The pathogenesis of AD is complex, and oxidative stress, which is involved in neuronal damage through various pathways, is considered to be a central part of AD pathogenesis. Therefore, we took advantage of the blood–brain barrier permeability of biogenic extracellular vesicles to load the high-performance antioxidant resveratrol (Res) and platinum (Pt) nanoparticles with multiple enzymatic activities into the extracellular vesicles and then deliver the 'Trojan horses' to the central nervous system to exert synergistic antioxidant effects. In this study, Res-Pt@EVs-RVG was designed to preferentially target the brain using rabies virus glycoprotein (RVG) peptides. In addition, the large photothermal effect of Pt nanoparticles increased the drug penetration and its high blood–brain barrier penetration ability was confirmed in vivo animal experiments. We found through multiple experiments that Res-Pt@EVs-RVG was well absorbed by cells, reduced intracellular reactive oxygen levels, improved mitochondrial damage, and attenuated glial cell activation while reducing neuronal loss in the brains of AD mice and improving memory impairment in APP/PS1 mice. Our results suggest that a biogenic extracellular vesicles-based drug delivery strategy overcomes the disadvantage of poor drug penetration into the central nervous system (CNS) and provides a potential platform for the effective treatment of AD. [ABSTRACT FROM AUTHOR]