Self-Assembly of Poly-Adenine-Tailed CpG Oligonucleotide-Gold Nanoparticle Nanoconjugates with Immunostimulatory Activity
Self-Assembly of Poly-Adenine-Tailed CpG Oligonucleotide-Gold Nanoparticle Nanoconjugates with Immunostimulatory Activity
复制标题
具有免疫刺激活性的聚腺嘌呤尾 CpG 寡核苷酸-金纳米颗粒纳米缀合物的自组装
DOI：
10.1002/smll.201300903
复制
发表时间：
2014-01-29
期刊：
影响因子：
13.3
通讯作者：
Huang, Qing
中科院分区：
文献类型：
--
作者：
Chen, Nan;Wei, Min;Huang, Qing
合成的非甲基化胞嘧啶-鸟嘌呤（CpG）寡脱氧核苷酸（CpG ODN）具有高免疫刺激活性，已广泛用作感染、过敏和癌症等多种疾病的治疗工具。已经开发了多种纳米载体用于CpG ODN的细胞内递送，所述CpG ODN在其他情况下不可透过细胞膜。例如，先前的研究表明，金纳米颗粒（AuNPs）可以有效地将合成的巯基化CpG ODN递送到培养的细胞中并诱导促炎细胞因子的表达。然而，使用硫醇化CpG ODN修饰AuNP的必要性不可避免地使纳米缀合物的合成复杂化并增加成本。展示了一种新的方法，用于轻松组装AuNP-CpG纳米缀合物，以实现具有成本效益的药物递送。发现含有CpG基序和聚腺嘌呤（polyA）尾的非硫醇化的二嵌段ODN可以容易地在具有可控和可调密度的AuNP表面上自组装。这种纳米缀合物被有效地递送到RAW264.7细胞中，并以Toll样受体9（TLR 9）依赖性方式诱导免疫应答。在最佳条件下，polyA-CpG-AuNP显示出比其硫醇化对应物显著更高的免疫刺激活性。此外，CpG-AuNP的免疫刺激活性可以通过改变polyA尾的长度来调节。通过使用聚A尾CpG-AuNP纳米缀合物证明了小鼠中免疫应答的体内诱导。
Synthetic unmethylated cytosine–guanine (CpG) oligodeoxynucleotides (CpG ODNs) possess high immunostimulatory activity and have been widely used as a therapeutic tool for various diseases including infection, allergies, and cancer. A variety of nanocarriers have been developed for intracellular delivery of CpG ODNs that are otherwise nonpermeable through the cellular membrane. For example, previous studies showed that gold nanoparticles (AuNPs) could efficiently deliver synthetic thiolated CpG ODNs into cultured cells and induce expression of proinflammatory cytokines. Nevertheless, the necessity of using thiolated CpG ODNs for the modification of AuNPs inevitably complicates the synthesis of the nanoconjugates and increases the cost. A new approach is demonstrated for facile assembly of AuNP‐CpG nanoconjugates for cost‐effective drug delivery. It is found that non‐thiolated, diblock ODNs containing a CpG motif and a poly‐adenine (polyA) tail can readily self‐assemble on the surface of AuNPs with controllable and tunable density. Such nanoconjugates are efficiently delivered into RAW264.7 cells and induce immune response in a Toll‐like receptor 9 (TLR9)‐dependent manner. Under optimal conditions, polyA‐CpG‐AuNPs show significantly higher immunostimulatory activity than their thiolated counterpart. In addition, the immunostimulatory activity of CpG‐AuNPs can be modulated by varying the length of the polyA tail. In vivo induction of immune responses in mice is demonstrated by using polyA‐tailed CpG‐AuNP nanoconjugates.