An Engineered Biomimetic Nanoreactor With Cascade Functions for Targeted and Combinatorial Therapy of Ischemic Stroke.

Abstract

Ischemic stroke reperfusion injury is driven by oxidative stress and neuroinflammation, but current neuroprotective strategies suffer from poor targeting, limited functionality, and low blood‑-brain barrier (BBB) penetration. Herein, a multifunctional nanoplatform (RM@HPAN) is constructed: a hollow mesoporous Prussian blue core with multi‑enzyme mimetic activity, loaded with L‑arginine and butylphthalide, cloaked with red blood cell membrane for immune evasion, and modified with RVG‑29 for brain targeting. RM@HPAN exhibits ideal nanosize, pH‑responsive release, and robust ROS scavenging. It crosses a BBB model in vitro and boosts neuronal viability under oxygen‑-glucose deprivation/reoxygenation. In a mouse middle cerebral artery occlusion model, RM@HPAN targets ischemic regions, reduces infarct volume from 29.4% to 3.8%, improves neurological scores, and rebalances inflammatory cytokines (TNF‑α, IL‑6, IL‑10, TGF‑β1). Transcriptomic and proteomic analyses reveal that RM@HPAN suppresses cytokine‑cytokine receptor interaction and TNF signaling while activating Rap1/PI3K/Akt and Nrf2/HO‑1 pathways, thereby inhibiting apoptosis and oxidative stress. Biosafety assessments confirm good biocompatibility. Thus, RM@HPAN offers a promising translatable strategy for ischemic stroke.