Dahlman James E, Barnes Carmen, Khan Omar, Thiriot Aude, Jhunjunwala Siddharth, Shaw Taylor E, Xing Yiping, Sager Hendrik B, Sahay Gaurav, Speciner Lauren, Bader Andrew, Bogorad Roman L, Yin Hao, Racie Tim, Dong Yizhou, Jiang Shan, Seedorf Danielle, Dave Apeksha, Sandu Kamaljeet S, Webber Matthew J, Novobrantseva Tatiana, Ruda Vera M, Lytton-Jean Abigail K R, Levins Christopher G, Kalish Brian, Mudge Dayna K, Perez Mario, Abezgauz Ludmila, Dutta Partha, Smith Lynelle, Charisse Klaus, Kieran Mark W, Fitzgerald Kevin, Nahrendorf Matthias, Danino Dganit, Tuder Rubin M, von Andrian Ulrich H, Akinc Akin, Schroeder Avi, Panigrahy Dipak, Kotelianski Victor, Langer Robert, Anderson Daniel G
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Nat Nanotechnol. 2014 Aug;9(8):648-655. doi: 10.1038/nnano.2014.84. Epub 2014 May 11.
Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis.
功能失调的内皮细胞比体内任何其他组织导致的疾病都更多。小干扰RNA（siRNA）可通过同时持久沉默多个基因，帮助体内内皮细胞的研究和治疗，但高效的siRNA递送迄今仍具有挑战性。在这里，我们表明，由低分子量多胺和脂质制成的聚合物纳米颗粒可以高效地将siRNA递送至内皮细胞，从而促进体内多个内皮基因的同时沉默。与脂质或类脂质纳米颗粒不同，即使在内皮基因沉默所需的剂量下，这种制剂也不会显著降低肝细胞或免疫细胞中的基因表达。这些纳米颗粒介导了迄今为止报道的最持久的非肝脏沉默，并促进了在血管通透性、肺气肿、原发性肿瘤生长和转移的小鼠模型中修饰内皮功能的siRNA的递送。
