Influenza A virus mimetic nanoparticles trigger selective cell uptake
Influenza A virus mimetic nanoparticles trigger selective cell uptake
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DOI：
10.1073/pnas.1902563116
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发表时间：
2019-05-14
影响因子：
11.1
通讯作者：
Goepferich, Achim
中科院分区：
文献类型：
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作者：
Figueroa, Sara Maslanka;Veser, Anika;Goepferich, Achim
靶细胞特异性差是目前用于生物医学应用的纳米粒子（NP）的主要缺点。它会导致偏离目标地点的重大物质损失以及预期交付地点的可用性较差。为了克服这一限制，我们设计了能够以类似病毒的方式识别细胞的颗粒。作为蓝图，我们选择了甲型流感病毒颗粒的典型机制，其中靶细胞的胞外酶促血凝素激活是与二级靶结构结合的强制性先决条件，该二级靶结构最终确认细胞身份并允许病毒的摄取。我们开发了纳米颗粒，使用血管紧张素 I (Ang-I) 作为配体来探测系膜细胞表面是否存在血管紧张素转换酶。这种初始相互作用将 Ang-I 酶促转化为二级配体血管紧张素 II (Ang-II)，后者有可能在第二阶段与 Ang-II 1 型受体 (AT1R) 结合。受体的存在确认了靶细胞的身份并通过内吞作用触发 NP 摄取。我们的病毒模拟纳米粒子表现出出色的靶细胞亲和力和皮摩尔亲和力，并且能够在 90% 仅携带 AT1R 的脱靶细胞存在的情况下选择性地识别这些细胞。我们的结果表明，病毒模拟细胞相互作用纳米颗粒的设计是增强纳米颗粒治疗和诊断应用特异性的有价值的策略。我们的主要和次要目标集特别适合识别在糖尿病肾病中发挥关键作用的系膜细胞，糖尿病肾病是肾衰竭的主要原因之一，目前尚无治疗方法。
Poor target cell specificity is currently a major shortcoming of nanoparticles (NPs) used for biomedical applications. It causes significant material loss to off-target sites and poor availability at the intended delivery site. To overcome this limitation, we designed particles that identify cells in a virus-like manner. As a blueprint, we chose a mechanism typical of influenza A virus particles in which ectoenzymatic hemagglutinin activation by target cells is a mandatory prerequisite for binding to a secondary target structure that finally confirms cell identity and allows for uptake of the virus. We developed NPs that probe mesangial cells for the presence of angiotensin-converting enzyme on their surface using angiotensin I (Ang-I) as a proligand. This initial interaction enzymatically transforms Ang-I to a secondary ligand angiotensin II (Ang-II) that has the potential to bind in a second stage to Ang-II type-1 receptor (AT1R). The presence of the receptor confirms the target cell identity and triggers NP uptake via endocytosis. Our virus-mimetic NPs showed outstanding target-cell affinity with picomolar avidities and were able to selectively identify these cells in the presence of 90% offtarget cells that carried only the AT1R. Our results demonstrate that the design of virus-mimetic cell interactive NPs is a valuable strategy to enhance NP specificity for therapeutic and diagnostic applications. Our set of primary and secondary targets is particularly suited for the identification of mesangial cells that play a pivotal role in diabetic nephropathy, one of the leading causes of renal failure, for which currently no treatment exists.