An engineered ROS-responsive cascade nanoplatform delays Alzheimer's disease progression via Nrf2/GPX4-mediated microglial functional reprogramming.

Alzheimer's disease (AD) is driven by a self-amplifying pathological network in which microglia-mediated neuroinflammation, oxidative stress, and cerebral iron dyshomeostasis are tightly interconnected. Here, we report a ROS-responsive, cascade-targeted nanoplatform (KMAI@NPs) engineered to intervene at this microglia-centered regulatory hub. The nanoplatform integrates an acetylsalicylic acid-modified dextran self-assembly core with PEGylated peptide modules for cascade targeting. By systematically optimizing the dextran molecular weight and acetylsalicylic acid grafting ratio, the self-assembly behavior and in vivo stability of the nanoplatform were rationally tuned. KMAI@NPs efficiently penetrate the blood-brain barrier, exhibit prolonged circulation, and selectively target activated microglia. Mechanistically, KMAI@NPs regulate microglial polarization and inhibit ferroptosis. In particular, given that M2-polarized microglia are more susceptible to ferroptosis, KMAI@NPs further protect these beneficial cells from ferroptotic injury through activation of the Nrf2/GPX4 axis, thereby preserving their anti-inflammatory and neuroprotective functions under inflammatory and iron-overload conditions. In APP/PS1 transgenic mice, KMAI@NPs markedly alleviate neuroinflammation, iron overload, amyloid pathology, and neuronal ultrastructural damage, resulting in significant cognitive improvement. This work establishes a microglia-centered, multitarget nanotherapeutic strategy that enables coordinated regulation of neuroinflammation, oxidative stress, and iron dyshomeostasis in AD.