Manturthi Shireesha, El-Sahli Sara, Bo Yuxia, Durocher Emma, Kirkby Melanie, Popatia Alyanna, Mediratta Karan, Daniel Redaet, Lee Seung-Hwan, Iqbal Umar, Côté Marceline, Wang Lisheng, Gadde Suresh
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
ACS Nanosci Au. 2024 Nov 15;4(6):416-425. doi: 10.1021/acsnanoscienceau.4c00040. eCollection 2024 Dec 18.
RNA-based agents (siRNA, miRNA, and mRNA) can selectively manipulate gene expression/proteins and are set to revolutionize a variety of disease treatments. Nanoparticle (NP) platforms have been developed to deliver functional mRNA or siRNA inside cells to overcome their inherent limitations. Recent studies have focused on siRNA to knock down proteins causing drug resistance or mRNA technology to introduce tumor suppressors. However, cancer needs multitargeted approaches to selectively manipulate multiple gene expressions/proteins. In this proof-of-concept study, we developed NPs containing Luc-mRNA and siRNA-GFP as model agents ((M+S)-NPs) and showed that NPs can simultaneously deliver functional mRNA and siRNA and impact the expression of two genes/proteins in vitro. Additionally, after in vivo administration, (M+S)-NPs successfully knocked down GFP while introducing luciferase into a TNBC mouse model, indicating that our NPs have the potential to develop RNA-based anticancer therapeutics. These studies pave the way to develop RNA-based, multitargeted approaches for complex diseases like cancer.
基于RNA的制剂（小干扰RNA、微小RNA和信使核糖核酸）能够选择性地调控基因表达/蛋白质表达，必将给多种疾病的治疗带来变革。人们已经开发出纳米颗粒（NP）平台，将功能性信使核糖核酸或小干扰RNA递送至细胞内，以克服它们固有的局限性。近期的研究聚焦于通过小干扰RNA敲低导致耐药性的蛋白质，或采用信使核糖核酸技术导入肿瘤抑制因子。然而，癌症需要多靶点方法来选择性地调控多个基因表达/蛋白质表达。在这项概念验证研究中，我们开发了含有荧光素酶信使核糖核酸和绿色荧光蛋白小干扰RNA作为模型制剂的纳米颗粒（（M+S）-NP），并证明纳米颗粒能够同时递送功能性信使核糖核酸和小干扰RNA，并在体外影响两个基因/蛋白质的表达。此外，在体内给药后，（M+S）-NP成功敲低了绿色荧光蛋白，同时将荧光素酶导入三阴性乳腺癌小鼠模型，这表明我们的纳米颗粒有潜力开发基于RNA的抗癌疗法。这些研究为开发针对癌症等复杂疾病的基于RNA的多靶点方法铺平了道路。
