2. Academic Validation
  3. Platelet-hitchhiking triiodothyronine nanoparticles for enhanced therapy of cerebral ischemia-reperfusion injury

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

  • J Colloid Interface Sci. 2025 Dec 15;700(Pt 1):138290. doi: 10.1016/j.jcis.2025.138290.
Madiha Zahra Syeda 1,  Guomin Su 2,  Yang Li 3,  He Bai 4,  Yong Liu 5,  Qingchun Mu 6,  Longguang Tang 7,  Wenhua Huang 8
Affiliations

Affiliations

  • 1 Affiliated Gaozhou People's Hospital, Guangdong Medical University, Maoming 525200, China; School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Affiliated Gaozhou People's Hospital, Guangdong Medical University, Maoming 525200, China.
  • 3 Department of Pharmacy, Center for Regenerative and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China.
  • 4 Affiliated Gaozhou People's Hospital, Guangdong Medical University, Maoming 525200, China; College of Life Science, Mudanjiang Medical University, Mudanjiang 157013, China.
  • 5 Department of Pathology, Mudanjiang Medical University, Mudanjiang 157013, China.
  • 6 Affiliated Gaozhou People's Hospital, Guangdong Medical University, Maoming 525200, China. Electronic address: muq@suda.edu.cn.
  • 7 Department of Pharmacy, Center for Regenerative and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China. Electronic address: tanglongguang@zju.edu.cn.
  • 8 School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: huangwenhua2009@139.com.
PMID: 40618479 DOI: 10.1016/j.jcis.2025.138290
Abstract

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.

Keywords

Autophagy; Cerebral ischemia; Platelets-hitchhiking nanoparticles; Thyroid hormone; Triiodothyronine (T3).

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