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Sustained delivery of siRNA/mesoporous silica nanoparticle (siRNA/MSN) complexes from nanofiber scaffolds for long-term gene silencing
Acta Biomaterialia ( IF 9.7 ) Pub Date : 2018-06-15 , DOI: 10.1016/j.actbio.2018.05.054
Coline Pinese , Junquan Lin , Ulla Milbreta , Mingqiang Li , Yucai Wang , Kam W. Leong , Sing Yian Chew

A low toxicity and efficient delivery system is needed to deliver small interfering RNAs (siRNA) in vitro and in vivo. The use of mesoporous silica nanoparticles (MSN) is becoming increasingly common due to its biocompatibility, tunable pore size and customizable properties. However, bolus delivery of siRNA/MSN complexes remains suboptimal, especially when a sustained and long-term administration is required. Here, we utilized electrospun scaffolds for sustained delivery of siRNA/MSN-PEI through surface adsorption and nanofiber encapsulation. As a proof-of-concept, we targeted collagen type I expression to modulate fibrous capsule formation. Surface adsorption of siRNA/MSN-PEI provided sustained availability of siRNA for at least 30 days in vitro. As compared to conventional bolus delivery, such scaffold-mediated transfection provided more effective gene silencing (p < 0.05). On the contrary, a longer sustained release was attained (at least 5 months) when siRNA/MSN-PEI complexes were encapsulated within the electrospun fibers. In vivo subcutaneous implantation and biodistribution analysis of these scaffolds revealed that siRNA remained localized up to ∼290 μm from the implants. Finally, a fibrous capsule reduction of ∼45.8 % was observed after 4 weeks in vivo as compared to negative scrambled siRNA treatment. Taken together, these results demonstrate the efficacy of scaffold-mediated sustained delivery of siRNA/MSN-PEI for long-term non-viral gene silencing applications.

Statement of Significance

The bolus delivery of siRNA/ Mesoporous Silica Nanoparticles (MSN) complexes shows high efficiency to silence protein agonists of tumoral processes as cancer treatments. However, in tissue engineering area, scaffold mediated delivery is desired to achieve a local and sustained release of therapeutics. We showed the feasibility and the efficacy of siRNA/MSN delivered from electrospun scaffolds through surface adsorption and nanofiber encapsulation. We showed that this method enhances siRNA transfection efficiency and sustained targeted proteins silencing in vitro and in vivo. As a proof of concept, in this study, we targeted collagen type I expression to modulate fibrous capsule formation. However this platform can be applied to the release and transfection of siRNA or miRNA in cancer and tissue engineering applications.



中文翻译:

从纳米纤维支架中持续递送siRNA /介孔二氧化硅纳米颗粒(siRNA / MSN)复合物以实现长期的基因沉默

需要低毒性和有效的递送系统以在体外体内递送小的干扰RNA(siRNA)。由于其生物相容性,可调节的孔径和可定制的特性,中孔二氧化硅纳米粒子(MSN)的使用正变得越来越普遍。然而,推注递送siRNA / MSN复合物仍然不是最理想的,尤其是在需要持续和长期给药的情况下。在这里,我们利用电纺支架通过表面吸附和纳米纤维封装来持续递送siRNA / MSN-PEI。作为概念验证,我们靶向I型胶原蛋白表达来调节纤维囊的形成。siRNA / MSN-PEI的表面吸附在体外至少30天提供了siRNA的持续可用性。与常规推注递送相比,这种支架介导的转染提供了更有效的基因沉默(p <0.05)。相反,将siRNA / MSN-PEI复合物封装在电纺纤维中可获得更长的持续释放(至少5个月)。这些支架的体内皮下植入和生物分布分析表明,siRNA仍可从植入物中定位至约290μm。最后,与阴性加扰的siRNA处理相比,在体内4周后观察到纤维囊减少约45.8%。综上所述,这些结果证明了支架介导的siRNA / MSN-PEI持续递送对于长期非病毒基因沉默应用的功效。

重要声明

siRNA /介孔二氧化硅纳米颗粒(MSN)复合物的大剂量递送显示出高效率,可以沉默作为癌症治疗方法的肿瘤过程中的蛋白激动剂。然而,在组织工程领域,需要支架介导的递送以实现治疗剂的局部和持续释放。我们展示了通过表面吸附和纳米纤维包封从电纺支架中递送siRNA / MSN的可行性和功效。我们发现,这种方法提高了siRNA转染效率和持续的针对性蛋白沉默在体外体内。作为概念的证明,在这项研究中,我们靶向I型胶原蛋白表达来调节纤维囊的形成。但是,该平台可用于癌症和组织工程应用中的siRNA或miRNA的释放和转染。

更新日期:2018-06-15
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