Bioengineered nanoparticles for siRNA delivery

Abstract

Short interfering RNA (siRNA) has been an important laboratory tool in the last two decades and has allowed researchers to better understand the functions of nonprotein-coding genes through RNA interference (RNAi). Although RNAi holds great promise for this purpose as well as for treatment of many diseases, efforts at using siRNA have been hampered by the difficulty of safely and effectively introducing it into cells of interest, both in vitro and in vivo. To overcome this challenge, many biomaterials and nanoparticles (NPs) have been developed and optimized for siRNA delivery, often taking cues from the DNA delivery field, although different barriers exist for these two types of molecules. In this review, we discuss general properties of biomaterials and nanoparticles that are necessary for effective nucleic acid delivery. We also discuss specific examples of bioengineered materials, including lipid-based NPs, polymeric NPs, inorganic NPs, and RNA-based NPs, which clearly illustrate the problems and successes in siRNA delivery.

Figure 1

siRNA faces several barriers during intracellular delivery. Representative biomaterials that are able to overcome these barriers are shown above, along with the particular strategy employed by that material.

Figure 2

Examples of classes of polymeric and lipidic biomaterials used for siRNA delivery.

Figure 3

Various approaches have been taken to lipid-based siRNA delivery. While some groups use rational design and focus on specific delivery aspects, such as lipid polymorphism leading to membrane fusion (A), others have employed high-throughput methods to screen through a wide array of different molecules to empirically determine the best structures (B–C). Reprinted by permission from Macmillan Publishers Ltd: Nature Biotechnology,^, copyright (2010) (A) and copyright (2008) (B–C).

Figure 4

Widely-used approaches to improving polymeric siRNA delivery include conjugation to PEG and targeting ligands (A) and introduction of disulfide bridges for controlled cytoplasmic release (B). Part A reprinted with permission from Christie, R. J.; Matsumoto, Y.; Miyata, K.; Nomoto, T.; Fukushima, S.; Osada, K.; Halnaut, J.; Pittella, F.; Kim, H. J.; Nishiyama, N.; Kataoka, K.: Targeted Polymeric Micelles for siRNA Treatment of Experimental Cancer by Intravenous Injection. ACS Nano 2012, 6, 5174–5189. Copyright (2012) American Chemical Society. Part B reprinted from Journal of Controlled Release, 150/2, van der Aa et al, Optimization of poly(amido amine)s as vectors for siRNA delivery, 177–186, Copyright (2011), with permission from Elsevier.

Figure 5

PLGA-b-PLL-g-PEG NPs contain siRNA, two drugs, and three ligands for targeting, cell penetration, and trafficking. Reprinted from Biomaterials, 33/2, Zhou et al, Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors, 177–186, Copyright (2012), with permission from Elsevier.