Mechanobiological modulation of blood-brain barrier permeability by laser stimulation of endothelial-targeted nanoparticles.
Mechanobiological modulation of blood-brain barrier permeability by laser stimulation of endothelial-targeted nanoparticles.
复制标题
通过激光刺激内皮靶向纳米粒子对血脑屏障渗透性进行机械生物学调节。
DOI：
10.1039/d2nr05062e
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发表时间：
2023
期刊：
影响因子：
6.7
通讯作者：
Qin,Zhenpeng
中科院分区：
文献类型：
--
作者：
Li,Xiaoqing;Cai,Qi;Wilson,BlakeA;Fan,Hanwen;Dave,Harsh;Giannotta,Monica;Bachoo,Robert;Qin,Zhenpeng
血脑屏障（BBB）维持脑内稳态的最佳环境，但阻止大多数治疗药物进入脑。可逆地增加BBB通透性的策略对于治疗脑疾病是必不可少的，并且是重要的临床前和转化兴趣的焦点。皮秒激光激发紧密连接靶向金纳米颗粒（AuNPs）产生纳米级的机械扰动，并诱导BBB渗透性（OptoBBB）的分级和可逆增加。在这里，我们通过显示靶向内皮糖蛋白导致比体外和体内靶向紧密连接高>10倍的靶向效率来推进该技术。通过紧密连接和糖蛋白靶向，我们证明了OptoBBB与Ca 2+，肌动蛋白聚合和ERK 1/2（细胞外信号调节蛋白激酶）磷酸化的瞬时升高和增殖相关。这些共同激活细胞骨架，导致细胞旁通透性增加。Ca 2+反应涉及内部Ca 2+耗竭和Ca 2+内流，并有机械敏感离子通道（TRPV 4，Piezo 1）的贡献。我们提供了对紧密连接蛋白（JAM-A）靶向和内皮（糖萼）靶向AuNPs的激发如何导致BBB通透性的类似机械生物学调节，同时靶向糖萼显著改善脑中的纳米颗粒积累的见解。这些结果对于指导这项技术在脑疾病治疗中的未来发展至关重要。
The blood–brain barrier (BBB) maintains an optimal environment for brain homeostasis but excludes most therapeutics from entering the brain. Strategies that reversibly increase BBB permeability are essential for treating brain diseases and are the focus of significant preclinical and translational interest. Picosecond laser excitation of tight junction-targeted gold nanoparticles (AuNPs) generates a nanoscale mechanical perturbation and induces a graded and reversible increase in BBB permeability (OptoBBB). Here we advanced this technique by showing that targeting endothelial glycoproteins leads to >10-fold higher targeting efficiency than targeting tight junctions both in vitro and in vivo. With both tight-junction and glycoprotein targeting, we demonstrate that OptoBBB is associated with a transient elevation and propagation of Ca2+, actin polymerization, and phosphorylation of ERK1/2 (extracellular signal-regulated protein kinase). These collectively activate the cytoskeleton resulting in increased paracellular permeability. The Ca2+ response involves internal Ca2+ depletion and Ca2+ influx with contributions from mechanosensitive ion channels (TRPV4, Piezo1). We provide insight into how the excitation of tight junction protein (JAM-A)-targeted and endothelial (glycocalyx)-targeted AuNPs leads to similar mechanobiological modulation of BBB permeability while targeting the glycocalyx significantly improves the nanoparticle accumulation in the brain. The results will be critical for guiding the future development of this technology for brain disease treatment.