Platelet-hitchhiking triiodothyronine nanoparticles for enhanced therapy of cerebral ischemia-reperfusion injury.

The emerging paradigm of bioinspired nanomedicine, exemplified by lipid nanoparticles and cellular drug carriers, has opened new avenues for targeting inaccessible tissues. Building on these advances, we present a platelet-hitchhiking nanoplatform engineered to overcome the blood-brain barrier (BBB) by leveraging vascular injury-responsive mechanisms. Recognizing the neuroprotective potential of thyroid hormones during ischemic crises, we designed fucoidan-decorated lipid nanoparticles (T-T3) that actively target P-selectin on activated platelets-molecular sentinels of cerebrovascular damage. This dual-functional design combines the BBB-penetrating capability of platelet trafficking with the mitochondrial-stabilizing effects of triiodothyronine (T3). In murine middle cerebral artery occlusion (MCAO) models, intravenously administered T-T3 exhibited higher ischemic brain accumulation compared to free drugs. The treatment conferred multidimensional neuroprotection: 40 % reduction in infarct volume (TTC quantification), 50 % decrease in Evans Blue extravasation indicating BBB repair, and mitigation of cerebral edema within 3 days (MRI imaging). Behavioral assessments revealed 2.2-fold improvement in motor coordination versus controls (Rotarod test). Mechanistically, T-T3 reshaped the inflammatory microenvironment by suppressing IL-6/TNF-α while elevating IL-10. Crucially, our cryo-ET analysis unveiled nanoparticle improved mitochondrial health through coordinated apoptosis inhibition and autophagy activation. This "pathology-responsive" design achieves high-level targeting specificity to ischemic lesions while sparing healthy tissue, validated through whole-body NIR-II fluorescence imaging. By integrating vascular interface engineering with organelle-level repair, our platform establishes a blueprint for nanotechnology-mediated treatment of neurological disorders, with potential applications extending to traumatic brain injury and neurodegeneration.