Two-dimensional vermiculite neuroprotectants attenuate multifaceted complications in ischemic stroke

Multifaceted complications underlie suboptimal outcomes after ischemic stroke. Conventional single-target therapies fail to address the complex spatiotemporal evolution of these complications. In this work, we designed and engineered two-dimensional vermiculite nanosheets (VM NSs) as a neuroprotective platform that integrates surface-catalytic reactive oxygen species (ROS) neutralization with protein kinase B (AKT)-centered signaling modulation to mitigate ischemic-cascade complications across the full course of post-stroke pathology. VM NSs exert dual-action efficacy through a hierarchically organized catalysis-signaling axis: immediate surface-mediated redox reactions neutralize ROS, as supported by computational modeling. Concomitantly, stable hydrophobic interactions with the AKT pleckstrin homology domain modulate anti-inflammatory signaling, as revealed by molecular dynamics simulations and validated by increased AKT phosphorylation in microglia. These actions are synergistically coupled: initial ROS scavenging creates a favorable microenvironment that facilitates subsequent AKT-mediated anti-inflammatory and pro-repair effects, whereas anti-inflammatory signaling limits secondary ROS generation from activated microglia, establishing a positive feedback loop that amplifies neuroprotection. Multimodal imaging and histopathology confirm that cerebrospinal fluid-delivered VM NSs achieve ischemic-penumbra-specific biodistribution through microglial endocytosis, reducing infarction, restoring cerebral perfusion, preserving blood-brain barrier integrity, and preventing hemorrhagic transformation. This therapeutic platform addresses key translational limitations of monotherapies by combining computationally supported surface catalysis with protein-level signaling modulation, offering an interdisciplinary paradigm for managing post-stroke complications throughout disease progression.