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Recent Advances in Mirna Delivery Systems University of Massachusetts Medical School eScholarship@UMMS Open Access Publications by UMMS Authors 2021-01-20 Recent Advances in miRNA Delivery Systems Ishani Dasgupta University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Molecular Biology Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, and the Therapeutics Commons Repository Citation Dasgupta I, Chatterjee A. (2021). Recent Advances in miRNA Delivery Systems. Open Access Publications by UMMS Authors. https://doi.org/10.3390/mps4010010. Retrieved from https://escholarship.umassmed.edu/oapubs/4554 Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Publications by UMMS Authors by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Perspective Recent Advances in miRNA Delivery Systems Ishani Dasgupta 1,† and Anushila Chatterjee 2,*,† 1 Horae Gene Therapy Center, Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605, USA; [email protected] 2 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: MicroRNAs (miRNAs) represent a family of short non-coding regulatory RNA molecules that are produced in a tissue and time-specific manner to orchestrate gene expression post-transcription. MiRNAs hybridize to target mRNA(s) to induce translation repression or mRNA degradation. Func- tional studies have demonstrated that miRNAs are engaged in virtually every physiological process and, consequently, miRNA dysregulations have been linked to multiple human pathologies. Thus, miRNA mimics and anti-miRNAs that restore miRNA expression or downregulate aberrantly ex- pressed miRNAs, respectively, are highly sought-after therapeutic strategies for effective manipula- tion of miRNA levels. In this regard, carrier vehicles that facilitate proficient and safe delivery of miRNA-based therapeutics are fundamental to the clinical success of these pharmaceuticals. Here, we highlight the strengths and weaknesses of current state-of-the-art viral and non-viral miRNA delivery systems and provide perspective on how these tools can be exploited to improve the outcomes of miRNA-based therapeutics. Keywords: miRNA; miRNA delivery; miRNA therapeutics; viral vectors; non-viral vectors 1. Introduction Citation: Dasgupta, I.; Chatterjee, A. Recent Advances in miRNA Delivery The spatiotemporal expression of microRNAs (miRNAs) in eukaryotes, a class of Systems. Methods Protoc. 2021, 4, 10. small single-stranded non-coding RNAs (18–25 nucleotides), plays a critical role in post- https://doi.org/10.3390/mps4010010 transcriptional gene regulation [1]. MiRNAs serve as modulators of gene expression by annealing to complementary sequences in the 30 or 50 untranslated regions (30UTR or 0 Received: 25 October 2020 5 UTR) of target mRNAs to block translation machinery and drive mRNA cleavage [2–5]. Accepted: 15 January 2021 Currently, 4571 human miRNAs (1917 precursors, 2654 mature) are annotated in public Published: 20 January 2021 repositories [6], and it is estimated that these non-coding RNAs regulate >30% of protein- coding genes involved in different biological processes [7,8]. Additionally, the availability Publisher’s Note: MDPI stays neutral of the human miRNA tissue atlas, which provides a comprehensive catalogue of tissue- with regard to jurisdictional claims in specific miRNA distribution and expression patterns, enables investigators to probe the published maps and institutional affil- physiological and pathological contributions of different miRNAs [9,10]. Several reports iations. implicate that dysregulated or dysfunctional miRNAs are associated with diverse human pathologies, including cancer, cardiovascular, neurodegenerative, inflammatory, genetic, and infectious diseases [11–17]. With the emerging evidence that miRNAs are involved in the onset and progression Copyright: © 2021 by the authors. of diverse biological anomalies, there has been a drastic surge of interest in miRNA-based Licensee MDPI, Basel, Switzerland. therapies over the last few decades [18,19]. Therapeutic approaches have been developed This article is an open access article to either suppress or restore the expression of disease-associated miRNAs (Table1). In distributed under the terms and circumstances where reduced miRNA expression drives the disease, miRNA mimics can conditions of the Creative Commons be used to restore their expression and function [19–22]. In contrast, anti-miRNAs (an- Attribution (CC BY) license (https:// tagomirs) are exploited to counteract the activity of upregulated miRNAs responsible for creativecommons.org/licenses/by/ disease [22–24]. However, the safe and efficient delivery of miRNA mimics or antagomirs 4.0/). Methods Protoc. 2021, 4, 10. https://doi.org/10.3390/mps4010010 https://www.mdpi.com/journal/mps Methods Protoc. 2021, 4, 10 2 of 18 to target tissues remains a significant challenge for miRNA-based therapies. Major limita- tions associated with miRNA delivery are susceptibility to degradation by nucleases, rapid clearance from blood, immunotoxicity, and low tissue permeability [25–29]. Chemical mod- ifications of miRNAs have significantly improved their stability and provided protection against nucleases [30–33]. Further, several oligonucleotide carriers have been developed to enhance stability and improve tissue penetration. In vivo viral and non-viral delivery miRNA methods, the challenges associated with the delivery methods, and strategies to circumvent them for a multitude of diseases, with a focus on cancer therapy, have been extensively reviewed [34–36]. These reviews also provide a detailed discussion on the miRNA expression profiles implicated in cancers. From this perspective, we emphasize the delivery aspects of miRNA in various human diseases and draw attention to some newly evolving miRNA delivery techniques that have not been covered in the recent reviews. Here, we provide a holistic overview of the viral and non-viral delivery systems developed to maximize miRNA therapeutic efficacy, highlight selected examples of their applications in various human diseases, comment on current clinical trials in the field, and offer perspectives on the future design and development of miRNA delivery technologies. Table 1. Selected list of miRNA-based therapeutics. Delivery System miRNA Target Disease Cellular Targets Reference Viral Systems Lentiviral-Based Delivery Systems Lentiviral miR-133b Spinal cord regeneration RhoA, Xylt1, Epha7, P2X, P2RX4 [37] Non-small-cell lung cancer RAS, MYC, HMGA2, CDC25A, Lentiviral let-7 [38] (NSCLC) CDK6, cyclin-D2 Adeno-associated virus miR-26a PIK3C2α/Akt/HIF-1α/VEGFA Liver tumor [39] (AAV) serotype 3 miR-122 Bcl-2, Bcl-w, Bcl-xl, and Mcl-1 Spinal and bulbar AAV serotype 9 miR-298 Androgen receptor [40] muscular atrophy Spinocerebellar ataxia type AAV serotype 5 miATXN3 ATXN3 [41] 3 (SCA3) Non-Viral Systems Lipid-Based Delivery Systems OPA1, TFAM, APIP, XIAP, and Lipid nanoparticle ds-miR-634 Pancreatic cancer [42] BIRC5, NRF2, LAMP2 Neutral liposome miR-34a Lung cancer BCL-2, c-Met, KRAS [43] Cationic liposome anti-miR-712 Atherosclerosis TIMP3, MMPs, ADAMs [44] ERK5, K-ras, CHEK2 miR-143 Cationic liposome Colorectal carcinoma MYCN, FOS, YES, FLI, cyclin D2, [44] miR-145 cyclin CDK3, MAP3K3, MAPK4K4 Cationic liposome miR-7 Lung cancer IRS-1, RAF-1, EGFR [45] Cationic liposome miR-29b Lung cancer CDK6, DNMT3B, MCL1 [46] Ionizable liposome miR-200c Lung cancer PRDX2, SESN1, GAPB/Nrf2 [47] Colon, breast, prostate, Ionizable cationic lipid miR-199b-5p glioblastoma, Hes-1 [48] nanoparticles medulloblastoma cancer Polymeric Delivery Systems Polyethyleneimines miR-145 Colon carcinoma c-Myc, ERK5 [49] (PEI) miR-33a PEI-PEG miR-34a Hepatocellular carcinoma SNAI1 [50] PACE polymer anti-miR-21 Glioblastoma PTEN [51] Polymer micelle anti-miR-21 Glioma PTEN [52] Inorganic Compound-Based Delivery Systems miR-29b BCL-2, MCL1 Carbonate apatite Colorectal cancers [53,54] miR-4689 KRAS, AKT1 Methods Protoc. 2021, 4, x FOR PEER REVIEW 3 of 18 MethodsPACE Protoc. polymer2021, 4, 10 anti-miR-21 Glioblastoma PTEN [51] 3 of 18 Polymer micelle anti-miR-21 Glioma PTEN [52] Inorganic Compound-Based Delivery Systems miR-29b BCL-2, MCL1 Carbonate apatite ColorectalTable cancers 1. Cont. [53,54] miR-4689 KRAS, AKT1 Delivery System miRNAExosome-Based Target D Diseaseelivery Systems Cellular Targets Reference Exosomes miR-199a-3p Exosome-BasedOvarian cancer Delivery Systemsc-Met, mTOR, IKKβ, and CD44 [55] ExosomeExosomes-GE11 miR-199a-3p Ovarian cancer c-Met, mTOR, IKKβ, and CD44 [55] let-7 Breast cancer HMGA2 [56] Exosome-GE11peptide peptide let-7 Breast cancer HMGA2 [56] ExosomeExosome miR-122 miR-122 Hepatocellular Hepatocellular carcinoma carcinoma ADAM10, ADAM10, IGF1R, IGF1R, CCNG1 CCNG1 [57] [57 ] Exosome miR-145 Lung cancer CDH2 [58] Exosome miR-145 Lung cancer CDH2 [58] 2. Virus Virus-Based-Based miRNA and Anti-miRNAAnti-miRNA Oligonucleotide Delivery Systems Genetically modified modified viruses can efficientlyefficiently transfertransfer desireddesired oligonucleotidesoligonucleotides intointo different tissuetissue typestypes
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