Elsevier

Journal of Controlled Release

Volume 172, Issue 3, 28 December 2013, Pages 962-974
Journal of Controlled Release

Review
Progress in microRNA delivery

https://doi.org/10.1016/j.jconrel.2013.09.015Get rights and content

Abstract

MicroRNAs (miRNAs) are non-coding endogenous RNAs that direct post-transcriptional regulation of gene expression by several mechanisms. Activity is primarily through binding to the 3′ untranslated regions (UTRs) of messenger RNAs (mRNA) resulting in degradation and translation repression. Unlike other small-RNAs, miRNAs do not require perfect base pairing, and thus, can regulate a network of broad, yet specific, genes. Although we have only just begun to gain insights into the full range of biologic functions of miRNA, their involvement in the onset and progression of disease has generated significant interest for therapeutic development. Mounting evidence suggests that miRNA-based therapies, either restoring or repressing miRNAs expression and activity, hold great promise. However, despite the early promise and exciting potential, critical hurdles often involving delivery of miRNA-targeting agents remain to be overcome before transition to clinical applications. Limitations that may be overcome by delivery include, but are not limited to, poor in vivo stability, inappropriate biodistribution, disruption and saturation of endogenous RNA machinery, and untoward side effects. Both viral vectors and nonviral delivery systems can be developed to circumvent these challenges. Viral vectors are efficient delivery agents but toxicity and immunogenicity limit their clinical usage. Herein, we review the recent advances in the mechanisms and strategies of nonviral miRNA delivery systems and provide a perspective on the future of miRNA-based therapeutics.

Section snippets

Discovery and action of miRNAs

MicroRNAs (miRNAs) are one of a growing number of non-coding RNA molecules that act within a cell [1], [2]. Noncoding RNAs include miRNA, small interfering RNA (siRNA), ribozymes, among others [3]. Both miRNA and siRNA interact with messenger RNA (mRNA), typically marking the mRNA for degradation as will be described in this review. Ribozymes are RNA molecules that bind to mRNA (or other RNAs) and catalyze the degradation of the RNA with no enzyme [4]. Ribozymes are the only RNAs in this class

MicroRNA therapeutic approaches

Using high-throughput techniques including miRNA microarrays, unique miRNAs expression profiles are being confirmed to mediate critical pathogenic processes in human disease [38], [41], [42]. These findings are rapidly being translated into recommendations targeting miRNA dysregulation. To translate these discoveries to viable therapies, appropriate, stable molecules must be designed and chemically modified poly(nucleic acids) are typically utilized for miRNA therapy. In addition to

Synthetic materials for miRNA and anti-miRNA oligonucleotide delivery

Synthetic materials have demonstrated potential as effective carriers for DNA and siRNA [75], [76], [77], [78], [79]. Under most circumstances, synthetic materials are cationic and condense negatively charged poly(nucleic acid)s through electrostatic interactions. Synthetic delivery systems have considerable advantages over viral-based vector due to the control of their molecular composition, simplified manufacturing, modification and analysis, tolerance for cargo sizes, and relatively lower

Future outlook: challenges and opportunities

Over the last several years, miRNA research has made amazingly rapid progress. But despite this, there is a belief that “RNAi is dead” [143] partly due to the departure from or reduction in emphasis on siRNA and miRNA by the pharmaceutical industry [144]. Few siRNA therapeutics and only two candidate miRNAs, SPC3649 (Santaris Pharma, Horsholm, Denmark) [145], [146], [147], [148], [149], [150], [151] a miR-122 antisense locked nucleic acid, and MRX34 (Mirna Therapeutics, Inc.) [152] a liposomal

Conclusion

Recent developments in the understanding of miRNA have suggested their therapeutic potential. But, the understanding of the biological genesis and activity will be the key to translation of this promising therapeutic class of molecules. Many of the challenges of delivering miRNA are similar, if not equivalent to siRNA and DNA, but some differences exist. The primary differences exist in the specificity of mRNAs that are repressed and the possibility to have promotion of expression directly

Acknowledgments

This review and our original miRNA research was conducted in a facility constructed with support from Research Facilities Improvement Program Grant (RR15482) from the National Centre for Research Resources (NCRR) of the National Institutes of Health (NIH). Our original miRNA delivery research has been funded, in part, by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award which is also supported by the NCRR (TR000050, RAG).

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