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A Brain-Targeted Nanozyme System for Alleviating Poststroke Neuroinflammation via Synergistic Antioxidant and
Boyang Wei1, Yu Wu1, Jiaming Zhou1
1Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou510282, China.
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.
