Mechanism for the endocytosis of spherical nucleic acid nanoparticle conjugates
Mechanism for the endocytosis of spherical nucleic acid nanoparticle conjugates
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DOI：
10.1073/pnas.1305804110
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发表时间：
2013-05-07
影响因子：
11.1
通讯作者：
Mirkin, Chad A.
中科院分区：
文献类型：
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作者：
Choi, Chung Hang J.;Hao, Liangliang;Mirkin, Chad A.
作为基因调控剂的核酸的细胞内递送通常需要使用阳离子载体或病毒载体，然而与细胞毒性或免疫应答相关的问题阻碍了它们作为治疗候选物的吸引力。球形核酸（SNA），聚阴离子结构组成的密集包装，高度定向的寡核苷酸共价连接到纳米粒子的表面，可以有效地进入超过50种不同的细胞类型的发现提出了一个潜在的策略，克服传统的转染剂的局限性。不幸的是，对SNA的内吞机制知之甚少，包括进入途径和涉及的特定蛋白。在这里，我们证明了SNA的快速细胞摄取动力学和细胞内转运源于寡核苷酸排列成3D结构，这支持它们通过脂筏依赖性、小窝介导的途径靶向A类清道夫受体和内吞作用。这些结果强化了这样的概念，即SNA可以用作治疗有效载荷和靶向结构，以接合线性寡核苷酸不容易进入的生物途径。
Intracellular delivery of nucleic acids as gene regulation agents typically requires the use of cationic carriers or viral vectors, yet issues related to cellular toxicity or immune responses hamper their attractiveness as therapeutic candidates. The discovery that spherical nucleic acids (SNAs), polyanionic structures comprised of densely packed, highly oriented oligonucleotides covalently attached to the surface of nanoparticles, can effectively enter more than 50 different cell types presents a potential strategy for overcoming the limitations of conventional transfection agents. Unfortunately, little is known about the mechanism of endocytosis of SNAs, including the pathway of entry and specific proteins involved. Here, we demonstrate that the rapid cellular uptake kinetics and intracellular transport of SNAs stem from the arrangement of oligonucleotides into a 3D architecture, which supports their targeting of class A scavenger receptors and endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. These results reinforce the notion that SNAs can serve as therapeutic payloads and targeting structures to engage biological pathways not readily accessible with linear oligonucleotides.