Translating Stroke Microenvironment Cues Into Materials Design: Intelligent Nanomaterials for Ischemic Stroke Therapy.

Ischemic stroke (IS), caused by cerebral blood vessel occlusion, leads to ischemia, hypoxia, and irreversible brain tissue damage. Current treatments primarily rely on thrombolytic agents like alteplase, urokinase, and streptokinase for rapid reperfusion. However, these therapies are limited by narrow therapeutic windows, rapid clearance, poor blood-brain barrier (BBB) penetration, off-target effects, and the complex ischemic microenvironment. These have led to increased interest in nanomaterial-based platforms to improve the precision and efficacy of IS treatment. The IS microenvironment, characterized by oxidative stress, inflammation, ionic imbalance, acidosis, and BBB disruption, provides valuable cues for designing responsive nanomaterials. Nanomaterials engineered to respond to reactive oxygen species, pH, enzymes, light, ultrasound, or magnetic fields can enable targeted drug delivery, controlled release, and multi-modal interventions, enhancing therapeutic precision. This review discusses the IS microenvironment, limitations of traditional therapies, recent advances in intelligent nanomaterials for IS treatment, and the major barriers that currently limit clinical translation.