Nanosac, a Noncationic and Soft Polyphenol Nanocapsule, Enables Systemic Delivery of siRNA to Solid Tumors.
Nanosac, a Noncationic and Soft Polyphenol Nanocapsule, Enables Systemic Delivery of siRNA to Solid Tumors.
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Nanosac是一种非阳离子和软质多酚纳米胶囊，能够将siRNA系统性递送至实体瘤。
DOI：
10.1021/acsnano.0c08694
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发表时间：
2021-03-23
期刊：
影响因子：
17.1
通讯作者：
Yeo Y
中科院分区：
文献类型：
--
作者：
Kim H;Yuk SA;Dieterly AM;Kwon S;Park J;Meng F;Gadalla HH;Cadena MJ;Lyle LT;Yeo Y
为了将siRNA全身递送至实体瘤，载体必须循环以避免过早降解、外渗和穿透肿瘤、进入靶细胞、运输至细胞内目的地并释放siRNA用于基因沉默。然而，现有的siRNA载体，其通常表现出正电荷，达不到这些要求的大幅度;因此，siRNA到肿瘤的全身递送仍然是一个重大的挑战。为了克服现有方法的局限性，我们开发了一种siRNA载体，称为“Nanosac”，一种非阳离子软多酚纳米胶囊。通过用siRNA和聚多巴胺顺序涂覆介孔二氧化硅纳米颗粒（MSN），然后去除牺牲的MSN核心来产生负载siRNA的Nanosac。Nanosac募集血清白蛋白，选择小窝介导的内吞作用进入肿瘤细胞，并有效地沉默靶基因。与硬质对应物相比，Nanosac的柔软性改善了外渗和渗透到肿瘤中。作为靶向PD-L1的siRNA载体，Nanosac通过免疫检查点阻断诱导CT 26肿瘤生长的显著衰减。这些结果支持Nanosac在用于实体瘤治疗的siRNA的全身递送中的效用。
For systemic delivery of siRNA to solid tumors, the carrier must circulate avoiding premature degradation, extravasate and penetrate tumors, enter target cells, traffic to the intracellular destination, and release siRNA for gene silencing. However, existing siRNA carriers, which typically exhibit positive charges, fall short of these requirements by a large margin; thus, systemic delivery of siRNA to tumors remains a significant challenge. To overcome the limitations of existing approaches, we have developed a carrier of siRNA, called “Nanosac,” a non-cationic soft polyphenol nanocapsule. A siRNA-loaded Nanosac is produced by sequential coating of mesoporous silica nanoparticles (MSN) with siRNA and polydopamine, followed by removal of the sacrificial MSN core. The Nanosac recruits serum albumin, co-opts caveolae-mediated endocytosis to enter tumor cells, and efficiently silences target genes. The softness of Nanosac improves extravasation and penetration into tumors compared to its hard counterpart. As a carrier of siRNA targeting PD-L1, Nanosac induces a significant attenuation of CT26 tumor growth by immune checkpoint blockade. These results support the utility of Nanosac in the systemic delivery of siRNA for solid tumor therapy.
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