Reprogramming the oxidative microenvironment: Antioxidant nanoplatforms for central nervous system repair

Acute central nervous system (CNS) injuries-such as ischemic stroke, traumatic brain injury (TBI), and spinal cord injury (SCI)-trigger a severe, self-reinforcing oxidative microenvironment. This reactive oxygen species (ROS)-driven cascade accelerates secondary injury mechanisms, including sustained neuroinflammation, blood-brain and blood-spinal cord barrier (BBB/BSCB) disruption, and irreversible mitochondrial dysfunction, ultimately forming a hostile niche that impedes spontaneous neural repair. While current clinical modalities address the primary physical or ischemic insults, they largely fail to mitigate this persistent oxidative stress. Furthermore, conventional small-molecule antioxidants are severely limited by poor pharmacokinetic profiles, inefficient barrier penetration, and an inability to provide spatiotemporally controlled ROS scavenging. To overcome these therapeutic bottlenecks, advanced antioxidant nanoplatforms have emerged as active regulators of the injury milieu. This review comprehensively examines the design principles of next-generation nanotherapeutics, highlighting strategies such as receptor-mediated transcytosis for active barrier traversal, stimuli-responsive mechanisms for on-site activation, and the integration of multi-catalytic inorganic nanozymes for subcellular precision. Beyond stoichiometric ROS scavenging, these platforms facilitate precise redox modulation that reprograms cellular fate. We detail how restoring redox homeostasis promotes the crucial M1-to-M2 polarization of microglia/macrophages, preserves mitochondrial integrity against apoptotic cascades, and creates a permissive microenvironment conducive to axonal regeneration and remyelination across stroke, TBI, and SCI models. Finally, we outline the critical translational challenges that must be addressed to transition these nanoplatforms into clinical practice, emphasizing the need for long-term biodistribution and immunotoxicity profiling, refined pharmacokinetic/pharmacodynamic (PK/PD) modeling, and the establishment of scalable, Good Manufacturing Practice (GMP)-compatible protocols.