A Brain-Targeted Nanozyme System for Alleviating Poststroke Neuroinflammation via Synergistic Antioxidant and Anti-inflammatory Mechanisms.

Abstract

Ischemic stroke (IS) is severely aggravated by oxidative stress and neuroinflammation, while the blood-brain barrier (BBB) poses a major obstacle to effective therapy. Herein, we developed a brain-targeted nanozyme system (TLNP@Pt/Fe3O4) by encapsulating Pt/Fe3O4 nanozymes into T7 peptide-modified lipid nanoparticles. Pt/Fe3O4 exhibited stable multienzymatic activities (SOD/CAT/POD-like) and favorable biocompatibility. Mediated by T7 peptide targeting, the nanoparticle efficiently penetrated the BBB, enhanced cellular uptake in microglia, and reduced nontarget organ accumulation. In vitro experiments demonstrated that TLNP@Pt/Fe3O4 effectively scavenged reactive oxygen species (ROS), reversed proinflammatory microglial polarization, and inhibited neuronal apoptosis. In a mouse model of transient middle cerebral artery occlusion (tMCAO), TLNP@Pt/Fe3O4 alleviated cerebral infarct and edema, while improving neurological and spatial cognitive functions. Mechanistically, scRNA-Seq showed that the nanozyme synergistically regulated redox homeostasis and the inflammatory microenvironment through the PI3K/AKT signaling pathways. Integrating targeted delivery, multienzymatic catalysis, and multitarget regulation, TLNP@Pt/Fe3O4 provides a promising and translatable therapeutic strategy for IS.