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Review

Innovative developments and emerging technologies in RNA therapeutics

ORCID Icon, , , , , , , , , ORCID Icon & ORCID Icon show all
Pages 313-332 | Received 18 Aug 2021, Accepted 06 Jan 2022, Published online: 19 Feb 2022

References

  • Zamecnik PC, Stephenson ML. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Nat Acad Sci. 1978;75:280–284.
  • Crooke ST, Liang XH, and Baker BF, et al. Antisense Technology: a Review. J Biol Chem. 2021;296 100416 .
  • Shen X, Corey DR. Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. 2018;46:1584–1600.
  • Crooke ST, Witztum JL, Bennett CF, et al. RNA-Targeted Therapeutics. Cell Metab. 2018;27:714–739.
  • O’Rourke JR, Swanson MS. Mechanisms of RNA-mediated disease. J Biol Chem. 2009;284:7419–7423.
  • Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233.
  • Havens MA, Hastings ML. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 2016;44:6549–6563.
  • Havens MA, Duelli DM, Hastings ML. Targeting RNA splicing for disease therapy. Wiley Interdiscip Rev RNA. 2013;4(3):247–266.
  • Keefe AD, Pai S, Ellington A. Aptamers as therapeutics. Nat Rev Drug Discov. 2010;9:537–550.
  • Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19:673–694.
  • Crooke ST, Wang S, Vickers TA, et al. Cellular uptake and trafficking of antisense oligonucleotides. Nat Biotechnol. 2017;35:230–237.
  • Iwamoto N, Butler DCD, Svrzikapa N, et al. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat Biotechnol. 2017;35:845–851.
  • Featherston AL, Kwon Y, Pompeo MM, et al. Catalytic asymmetric and stereodivergent oligonucleotide synthesis. Science. 2021;371:702–707.
  • Li M, Lightfoot HL, Halloy F, et al. Synthesis and cellular activity of stereochemically-pure 2’-O-(2-methoxyethyl)-phosphorothioate oligonucleotides. Chem Comm. 2017;53:541–544.
  • Østergaard ME, De Hoyos CL, Wan WB, et al. Understanding the effect of controlling phosphorothioate chirality in the DNA gap on the potency and safety of gapmer antisense oligonucleotides. Nucleic Acids Res. 2020;48:1691–1700.
  • Byrne M, Vathipadiekal V, Apponi L, et al. Stereochemistry enhances potency. Efficacy, and Durability of Malat1 Antisense Oligonucleotides in Vitro and in Vivo in Multiple Species Translational Vision Sci Technol. 2021;10:23.
  • Dragovich PS, Adhikari P, Blake RA, et al. Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα). Bioorg Med Chem Lett. 2020;30:126907.
  • Goyenvalle A, Griffith G, Babbs A, et al. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat Med. 2015;21:270–275.
  • Geary RS. Antisense oligonucleotide pharmacokinetics and metabolism. Expert opinion on drug metabolism & toxicology . 2009;5:381–391.
  • Nishina K, Piao W, Yoshida-Tanaka K, et al. DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing. Nat Commun. 2015;6:7969.
  • Yoshioka K, Kunieda T, Asami Y, et al. Highly efficient silencing of microRNA by heteroduplex oligonucleotides. Nucleic Acids Res. 2019;47:7321–7332.
  • Ono D, Asada K, Yui D, et al. Separation-related rapid nuclear transport of DNA/RNA heteroduplex oligonucleotide: unveiling distinctive intracellular trafficking. Molecular Therapy - Nucleic Acids. 2021;23:1360–1370.
  • Kuwahara H, Song J, Shimoura T, et al. Modulation of blood-brain barrier function by a heteroduplex oligonucleotide in vivo. Sci Rep. 2018;8:4377.
  • Nagata T, Dwyer CA, Yoshida-Tanaka K, et al. Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood-brain barrier and knock down genes in the rodent CNS. Nat Biotechnol. 2021;39:1529–1536.
  • Zahid M, Robbins P. Cell-Type specific penetrating peptides: therapeutic promises and challenges. Molecules. 2015;20:13055.
  • Pae J, Pooga M. Peptide-mediated delivery: an overview of pathways for efficient internalization. Ther Deliv. 2014;5:1203–1222.
  • Tung C-H, Stein S. Preparation and applications of peptide− oligonucleotide conjugates. Bioconjug Chem. 2000;11:605–618.
  • Prater CE, Miller PS. 3 ‘-methylphosphonate-modified oligo-2 ‘-O-methylribonucleotides and their Tat peptide conjugates: uptake and stability in mouse fibroblasts in culture. Bioconjug Chem. 2004;15:498–507.
  • Turner JJ, Arzumanov AA, Gait MJ. Synthesis, cellular uptake and HIV-1 Tat-dependent trans-activation inhibition activity of oligonucleotide analogues disulphide-conjugated to cell-penetrating peptides. Nucleic Acids Res. 2005;33:27–42.
  • Eguchi A, Meade BR, Chang Y-C, et al. Efficient siRNA delivery into primary cells by a peptide transduction domain–dsRNA binding domain fusion protein. Nat Biotechnol. 2009;27:567–571.
  • Meade BR, Gogoi K, Hamil AS, et al. Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications. Nat Biotechnol. 2014;32:1256–1261.
  • Knerr L, Prakash TP, Lee R, et al. Glucagon like peptide 1 receptor agonists for targeted delivery of antisense oligonucleotides to pancreatic beta cell. J Am Chem Soc. 2021;143:3416–3429.
  • Sugo T, Terada M, Oikawa T, et al. Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release. 2016;237:1–13.
  • Arnold A, Malek-Adamian E, and Le P, et al. Antibody-antisense oligonucleotide conjugate downregulates a key gene in glioblastoma stem cells. Mol Ther Nucleic Acids. 2018;11:187–194.
  • Satake N, Duong C, Yoshida S, et al. Novel targeted therapy for precursor b cell acute lymphoblastic leukemia: anti-cd22 antibody-mxd3 antisense oligonucleotide conjugate. Mol Med. 2016;22:632–642.
  • Zavoiura O, Brunner B, Casteels P, et al. Nanobody–siRNA Conjugates for Targeted Delivery of siRNA to Cancer Cells. Mol Pharm. 2021;18:1048–1060.
  • Debacker AJ, Voutila J, Catley M, et al. Delivery of oligonucleotides to the liver with galnac: from research to registered therapeutic drug. Mol Ther. 2020;28:1759–1771.
  • Orellana EA, Tenneti S, Rangasamy L, et al. FolamiRs: ligand-targeted, vehicle-free delivery of microRNAs for the treatment of cancer. Sci Transl Med. 2017;9. DOI:10.1126/scitranslmed.aam9327
  • Juliano RL. Intracellular trafficking and endosomal release of oligonucleotides: what we know and what we don’t. Nucleic Acid Ther. 2018;28:166–177.
  • Ming X, Carver K, Fisher M, et al. The small molecule Retro-1 enhances the pharmacological actions of antisense and splice switching oligonucleotides. Nucleic Acids Res. 2013;41:3673–3687.
  • Yang B, Ming X, Cao C, et al. High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides. Nucleic Acids Res. 2015;43:1987–1996.
  • Stein CA, Hansen JB, Lai J, et al. Efficient gene silencing by delivery of locked nucleic acid antisense oligonucleotides, unassisted by transfection reagents. Nucleic Acids Res. 2010;38(1):e3–e3.
  • Brown CR, Gupta S, Qin J, et al. Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates. Nucleic Acids Res. 2020;48:11827–11844.
  • Linnane E, Davey P, Zhang P, et al. Differential uptake, kinetics and mechanisms of intracellular trafficking of next-generation antisense oligonucleotides across human cancer cell lines. Nucleic Acids Res. 2019;47:4375–4392.
  • Gilleron J, Querbes W, Zeigerer A, et al. Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat Biotechnol. 2013;31:638–646.
  • Buntz A, Killian T, Schmid D, et al. Quantitative fluorescence imaging determines the absolute number of locked nucleic acid oligonucleotides needed for suppression of target gene expression. Nucleic Acids Res. 2018;47:953–969.
  • He C, Migawa MT, Chen K, et al. High-resolution visualization and quantification of nucleic acid–based therapeutics in cells and tissues using Nanoscale secondary ion mass spectrometry (NanoSIMS). Nucleic Acids Res. 2020;49:1–14.
  • Crooke ST, Vickers TA, Liang X-H. Phosphorothioate modified oligonucleotide–protein interactions. Nucleic Acids Res. 2020;48:5235–5253.
  • Crooke ST, Seth PP, Vickers TA, et al. The interaction of phosphorothioate-Containing RNA targeted drugs with proteins is a critical determinant of the therapeutic effects of these agents. J Am Chem Soc. 2020;142:14754–14771.
  • Liang X-H, Sun H, Shen W, et al. Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages. Nucleic Acids Res. 2015;43:2927–2945.
  • Miller CM, Donner AJ, Blank EE, et al. Stabilin-1 and Stabilin-2 are specific receptors for the cellular internalization of phosphorothioate-modified antisense oligonucleotides (ASOs) in the liver. Nucleic Acids Res. 2016;44:2782–2794.
  • Wang S, Allen N, Vickers TA, et al. Cellular uptake mediated by epidermal growth factor receptor facilitates the intracellular activity of phosphorothioate-modified antisense oligonucleotides. Nucleic Acids Res. 2018;46:3579–3594.
  • Liang X-H, Sun H, Hsu C-W, et al. Golgi-endosome transport mediated by M6PR facilitates release of antisense oligonucleotides from endosomes. Nucleic Acids Res. 2019;48:1372–1391.
  • Vickers TA, Migawa MT, Seth PP, et al. Interaction of ASOs with PC4 Is highly influenced by the cellular environment and ASO chemistry. J Am Chem Soc. 2020;142:9661–9674.
  • Hyjek-Składanowska M, Vickers TA, Napiórkowska A, et al. Origins of the increased affinity of phosphorothioate-modified therapeutic nucleic acids for proteins. J Am Chem Soc. 2020;142:7456–7468.
  • Zimmermann TS, Karsten V, Chan A, et al. Clinical proof of concept for a novel hepatocyte-targeting GalNAc-siRNA conjugate. Mol Ther. 2017;25:71–78.
  • Balwani M, Sardh E, Ventura P, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382:2289–2301.
  • Garrelfs S, Frishberg Y, Hulton S, et al. LB002 Illuminate-A, a phase 3 study of Lumasiran, an investigational RNAi therapeutic, in children and adults with primary hyperoxaluria type 1 (PH1). Nephrol Dialysis Transplantation. 2020;35. DOI:10.1093/ndt/gfaa146.LB002
  • Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382:1520–1530.
  • Osborn MF, Khvorova A. Improving siRNA delivery in vivo through lipid conjugation. Nucleic Acid Ther. 2018;28:128–136.
  • Wolfrum C, Shi S, Jayaprakash KN, et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol. 2007;25:1149–1157.
  • Biscans A, Coles A, Haraszti R, et al. Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo. Nucleic Acids Res. 2018;47:1082–1096.
  • Hassler MR, Turanov AA, Alterman JF, et al. Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo. Nucleic Acids Res. 2018;46:2185–2196.
  • Bartlett DW, Davis ME. Effect of siRNA nuclease stability on the in vitro and in vivo kinetics of siRNA-mediated gene silencing. Biotechnol Bioeng. 2007;97:909–921.
  • Layzer JM, McCaffrey AP, Tanner AK, et al. In vivo activity of nuclease-resistant siRNAs. RNA. 2004;10:766–771.
  • Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature. 2004;432:173–178.
  • Hu B, Zhong L, Weng Y, et al. Therapeutic siRNA: state of the art. Signal Transduct Target Ther. 2020;5:101.
  • Allerson CR, Sioufi N, Jarres R, et al. Fully 2‘-Modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J Med Chem. 2005;48:901–904.
  • Foster DJ, Brown CR, Shaikh S, et al. Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates. Mol Ther. 2018;26:708–717.
  • Eckstein F. Phosphorothioates, essential components of therapeutic oligonucleotides. Nucleic Acid Ther. 2014;24:374–387.
  • Biscans A, Caiazzi J, Davis S, et al. The chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy. Nucleic Acids Res. 2020;48:7665–7680.
  • Braasch DA, Jensen S, Liu Y, et al. RNA interference in mammalian cells by chemically-modified RNA. Biochemistry. 2003;42:7967–7975.
  • Shen W, De Hoyos CL, Sun H, et al. Acute hepatotoxicity of 2′ fluoro-modified 5–10–5 gapmer phosphorothioate oligonucleotides in mice correlates with intracellular protein binding and the loss of DBHS proteins. Nucleic Acids Res. 2018;46:2204–2217.
  • Sakamuri S, Eltepu L, Liu D, et al. Impact of phosphorothioate chirality on double-stranded siRNAs: a systematic evaluation of stereopure siRNA designs. Chembiochem. 2020;21:1304–1308.
  • Wu SY, Yang X, Gharpure KM, et al. 2’-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nat Commun. 2014;5:3459.
  • Kumar P, Parmar RG, Brown CR, et al. 5′-Morpholino modification of the sense strand of an siRNA makes it a more effective passenger. Chem Comm. 2019;55:5139–5142.
  • Ma JB, Yuan YR, Meister G, et al. Structural basis for 5’-end-specific recognition of guide RNA by the A. fulgidus Piwi protein. Nature. 2005;434:666–670.
  • Frank F, Sonenberg N, Nagar B. Structural basis for 5’-nucleotide base-specific recognition of guide RNA by human AGO2. Nature. 2010;465:818–822.
  • Bramsen JB, Pakula MM, Hansen TB, et al. A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects. Nucleic Acids Res. 2010;38:5761–5773.
  • Janas MM, Schlegel MK, Harbison CE, et al. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity. Nat Commun. 2018;9:723.
  • Malek-Adamian E, Fakhoury J, Arnold AE, et al. Effect of Sugar 2′,4′-modifications on gene silencing activity of siRNA duplexes. Nucleic Acid Ther. 2019;29:187–194.
  • Aurup H, Williams DM, Eckstein F. 2’-Fluoro and 2-amino-2’-deoxynucleoside 5’-triphosphates as substrates for T7 RNA polymerase. Biochemistry. 1992;31:9636–9641.
  • Mikami A, Erande N, Matsuda S, et al. Synthesis, chirality-dependent conformational and biological properties of siRNAs containing 5′-(R)- and 5′-(S)-C-methyl-guanosine. Nucleic Acids Res. 2020;48:10101–10124.
  • Akabane-Nakata M, Erande ND, Kumar P, et al. siRNAs containing 2′-fluorinated Northern-methanocarbacyclic (2′-F-NMC) nucleotides: in vitro and in vivo RNAi activity and inability of mitochondrial polymerases to incorporate 2′-F-NMC NTPs. Nucleic Acids Res. 2021;49:2435–2449.
  • Nanna AR, Kel’in AV, Theile C, et al. Generation and validation of structurally defined antibody–siRNA conjugates. Nucleic Acids Res. 2020;48:5281–5293.
  • Nuzzo S, Roscigno G, Affinito A, et al. Potential and challenges of aptamers as specific carriers of therapeutic oligonucleotides for precision medicine in cancer. Cancers (Basel). 2019;11:1521.
  • Klein D, Goldberg S, Theile CS, et al. Centyrin ligands for extrahepatic delivery of siRNA. Mol Ther. 2021;29:2053–2066.
  • Kubo T, Nishimura Y, Sato Y, et al. Sixteen different types of lipid-conjugated siRNAs containing saturated and unsaturated fatty acids and exhibiting enhanced RNAi potency. ACS Chem Biol. 2021;16:150–164.
  • Biscans A, Coles A, Echeverria D, et al. The valency of fatty acid conjugates impacts siRNA pharmacokinetics, distribution, and efficacy in vivo. J Control Release. 2019;302:116–125.
  • Osborn MF, Coles AH, Biscans A, et al. Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways. Nucleic Acids Res. 2018;47:1070–1081.
  • Biscans A, Caiazzi J, McHugh N, et al. Docosanoic acid conjugation to siRNA enables functional and safe delivery to skeletal and cardiac muscles. Mol Ther. 2021;29:1382–1394.
  • Dowdy SF. Overcoming cellular barriers for RNA therapeutics. Nat Biotechnol. 2017;35:222–229.
  • Good L, Awasthi SK, Dryselius R, et al. Bactericidal antisense effects of peptide-PNA conjugates. Nat Biotechnol. 2001;19:360–364.
  • Sully EK, Geller BL. Antisense antimicrobial therapeutics. Curr Opin Microbiol. 2016;33:47–55.
  • Geller BL, Li L, Martinez F, et al. Morpholino oligomers tested in vitro, in biofilm and in vivo against multidrug-resistant Klebsiella pneumoniae. J Antimicrob Chemother. 2018;73:1611–1619.
  • Dryselius R, Aswasti SK, Rajarao GK, et al. The translation start codon region is sensitive to antisense PNA inhibition in Escherichia coli. Oligonucleotides. 2003;13:427–433.
  • Deere J, Iversen P, Geller BL. Antisense phosphorodiamidate morpholino oligomer length and target position effects on gene-specific inhibition in Escherichia coli. Antimicrob Agents Chemother. 2005;49:249–255.
  • Goltermann L, Yavari N, Zhang M, et al. PNA length restriction of antibacterial activity of Peptide-PNA conjugates in Escherichia coli through effects of the inner membrane. Front Microbiol. 2019;10:1032.
  • Daly SM, Sturge CR, Marshall-Batty KR, et al. Antisense inhibitors retain activity in pulmonary models of burkholderia infection. ACS Infect Dis. 2018;4(5):806–814.
  • Pfeiffer V, Papenfort K, Lucchini S, et al. Coding sequence targeting by MicC RNA reveals bacterial mRNA silencing downstream of translational initiation. Nat Struct Mol Biol. 2009;16(8):840–846.
  • Xue XY, Mao XG, Zhou Y, et al. Advances in the delivery of antisense oligonucleotides for combating bacterial infectious diseases. Nanomedicine. 2018;14(3):745–758.
  • Andrews JM. Determination of minimum inhibitory concentrations. J Antimicrob Chemother. 2001;48(1):5–16. Suppl.
  • Greenberg DE, Marshall-Batty KR, Brinster LR, et al. Antisense phosphorodiamidate morpholino oligomers targeted to an essential gene inhibit Burkholderia cepacia complex. J Infect Dis. 2010;201:1822–1830.
  • Howard JJ, Sturge CR, Moustafa DA, et al. Inhibition of Pseudomonas aeruginosa by peptide-conjugated phosphorodiamidate morpholino oligomers. Antimicrob Agents Chemother. 2017;61. DOI:10.1128/AAC.01938-16
  • Geller BL, Marshall-Batty K, Schnell FJ, et al. Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo. J Infect Dis. 2013;208:1553–1560.
  • Barkowsky G, Lemster AL, Pappesch R, et al. Influence of different cell-penetrating peptides on the antimicrobial efficiency of PNAs in Streptococcus pyogenes. Mol Ther Nucleic Acids. 2019;18:444–454.
  • Puckett SE, Reese KA, Mitev GM, et al. Bacterial resistance to antisense peptide phosphorodiamidate morpholino oligomers. Antimicrob Agents Chemother. 2012;56:6147–6153.
  • Ghosal A, Vitali A, Stach JE, et al. Role of SbmA in the uptake of peptide nucleic acid (PNA)-peptide conjugates in E. coli. ACS Chem Biol. 2013;8:360–367.
  • Hansen AM, Bonke G, Larsen CJ, et al. Antibacterial peptide nucleic acid-antimicrobial peptide (PNA-AMP) conjugates: antisense targeting of fatty acid biosynthesis. Bioconjug Chem. 2016;27:863–867.
  • Li LC, Okino ST, Zhao H, et al. Small dsRNAs induce transcriptional activation in human cells. Proc Natl Acad Sci U S A. 2006;103:17337–17342.
  • Huang V, Qin Y, Wang J, et al. RNAa is conserved in mammalian cells. PLoS One. 2010;5:e8848.
  • Turunen MP, Lehtola T, Heinonen SE, et al. Efficient regulation of VEGF expression by promoter-targeted lentiviral shRNAs based on epigenetic mechanism: a novel example of epigenetherapy. Circ Res. 2009;105:604–609.
  • Meng X, Jiang Q, Chang N, et al. Small activating RNA binds to the genomic target site in a seed-region-dependent manner. Nucleic Acids Res. 2016;44:2274–2282.
  • Voutila J, Reebye V, Roberts TC, et al. Development and mechanism of small activating RNA targeting CEBPA, a novel therapeutic in clinical trials for liver cancer. Mol Ther. 2017;25:2705–2714.
  • Place RF, Noonan EJ, Földes-Papp Z, et al. Defining features and exploring chemical modifications to manipulate RNAa activity. Curr Pharm Biotechnol. 2010;11:518–526.
  • Janowski BA, Younger ST, Hardy DB, et al. Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat Chem Biol. 2007;3:166–173.
  • Portnoy V, Lin SH, Li KH, et al. saRNA-guided Ago2 targets the RITA complex to promoters to stimulate transcription. Cell Res. 2016;26:320–335.
  • Chu Y, Yue X, Younger ST, et al. Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a non-coding transcript at the progesterone receptor promoter. Nucleic Acids Res. 2010;38:7736–7748.
  • Matsui M, Sakurai F, Elbashir S, et al. Activation of LDL receptor expression by small RNAs complementary to a noncoding transcript that overlaps the LDLR promoter. Chem Biol. 2010;17:1344–1355.
  • Matsui M, Chu Y, Zhang H, et al. Promoter RNA links transcriptional regulation of inflammatory pathway genes. Nucleic Acids Res. 2013;41:10086–10109.
  • Zhang X, Li H, Burnett JC, et al. The role of antisense long noncoding RNA in small RNA-triggered gene activation. Rna. 2014;20:1916–1928.
  • Zhao X, Reebye V, Hitchen P, et al. Mechanisms involved in the activation of C/EBPα by small activating RNA in hepatocellular carcinoma. Oncogene. 2019;38:3446–3457.
  • Yoon S, Rossi JJ. Therapeutic potential of small activating RNAs (saRNAs) in human cancers. Curr Pharm Biotechnol. 2018;19:604–610.
  • Huang KW, Reebye V, Czysz K, et al. Liver activation of hepatocellular nuclear factor-4α by small activating RNA rescues dyslipidemia and improves metabolic profile. Mol Ther Nucleic Acids. 2020;19:361–370.
  • Sarker D, Plummer R, Meyer T, et al. MTL-CEBPA, a small activating RNA therapeutic upregulating C/EBP-α, in patients with advanced liver cancer: a first-in-human, multicenter, open-label, phase i trial. Clin Cancer Res off J Am Assoc Cancer Res. 2020;26:3936–3946.
  • Ross JS, Sheehan CE, Fisher HAG, et al. Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer Res off J Am Assoc Cancer Res. 2003;9:6357–6362.
  • Silver DA, Pellicer I, Fair WR, et al. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res off J Am Assoc Cancer Res. 1997;3:81–85.
  • Seeman NC, Sleiman HF. DNA nanotechnology. Nat Rev Mater. 2017;3:17068.
  • Dey S, Fan C, Gothelf KV, et al. DNA origami. Nat Rev Method Primers. 2021;1:13.
  • Tikhomirov G, Petersen P, Qian L. Fractal assembly of micrometre-scale DNA origami arrays with arbitrary patterns. Nature. 2017;552:67–71.
  • Benson E, Mohammed A, Gardell J, et al. DNA rendering of polyhedral meshes at the nanoscale. Nature. 2015;523:441–444.
  • Rothemund PWK. Folding DNA to create nanoscale shapes and patterns. Nature. 2006;440:297–302.
  • Andersen ES, Dong M, Nielsen MM, et al. DNA origami design of dolphin-shaped structures with flexible tails. ACS Nano. 2008;2:1213–1218.
  • Jun H, Shepherd TR, Zhang K, et al. Automated sequence design of 3d polyhedral wireframe DNA origami with honeycomb edges. ACS Nano. 2019;13:2083–2093.
  • Goodman RP, Berry RM, Turberfield AJ. The single-step synthesis of a DNA tetrahedron. Chem Comm. 2004;1372–1373. DOI:10.1039/b402293a
  • Aldaye FA, Sleiman HF. Modular access to structurally switchable 3D discrete DNA assemblies. J Am Chem Soc. 2007;129:13376–13377.
  • Hu Q, Li H, Wang L, et al. DNA nanotechnology-enabled drug delivery systems. Chem Rev. 2019;119:6459–6506.
  • Chidchob P, Sleiman HF. Recent advances in DNA nanotechnology. Curr Opin Chem Biol. 2018;46:63–70.
  • Afonin KA, Dobrovolskaia MA, Church G, et al. Opportunities, barriers, and a strategy for overcoming translational challenges to therapeutic nucleic acid nanotechnology. ACS Nano. 2020;14:9221–9227.
  • Bujold KE, Lacroix A, Sleiman HF. DNA nanostructures at the interface with biology. Chem. 2018;4:495–521.
  • Walsh AS, Yin H, Erben CM, et al. DNA cage delivery to mammalian cells. ACS Nano. 2011;5:5427–5432.
  • Mirkin CA, Letsinger RL, Mucic RC, et al. A DNA-based method for rationally assembling nanoparticles into macroscopic materials. Nature. 1996;382:607–609.
  • Cutler JI, Auyeung E, Mirkin CA. Spherical nucleic acids. J Am Chem Soc. 2012;134:1376–1391.
  • Liu B, Liu J. Methods for preparing DNA-functionalized gold nanoparticles, a key reagent of bioanalytical chemistry. Anal Methods. 2017;9:2633–2643.
  • Kapadia CH, Melamed JR, Day ES. Spherical Nucleic Acid Nanoparticles: therapeutic Potential. BioDrugs: clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2018;32: 297–309.
  • Jiang S, Ge Z, and Mou S, et al. Designer DNA nanostructures for therapeutics. Chem. 2020;7: 1156–1179.
  • Wang S, Qin L, Yamankurt G, et al. Rational vaccinology with spherical nucleic acids. Proc Nat Acad Sci. 2019;116:10473–10481.
  • Zhang W, Meckes B, Mirkin CA. Spherical nucleic acids with tailored and active protein coronae. ACS Cent Sci. 2019;5:1983–1990.
  • Thai HBD, Kim K-R, Hong KT, et al. Kidney-targeted cytosolic delivery of siRNA using a small-sized mirror DNA tetrahedron for enhanced potency. ACS Cent Sci. 2020;6:2250–2258.
  • Lee H, Lytton-Jean AKR, Chen Y, et al. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery. Nat Nanotechnol. 2012;7:389–393.
  • Yamankurt G, Stawicki RJ, Posadas DM, et al. The effector mechanism of siRNA spherical nucleic acids. Proc Nat Acad Sci. 2020;117:1312–1320.
  • Rahman MA, Wang P, Zhao Z, et al. Systemic delivery of Bc12-Targeting siRNA by DNA nanoparticles suppresses cancer cell growth. Angew Chem. 2017;56:16023–16027.
  • Kusmierz CD, Bujold KE, Callmann CE, et al. Defining the design parameters for in vivo enzyme delivery through protein spherical nucleic acids. ACS Cent Sci. 2020;6:815–822.
  • Lacroix A, Edwardson TGW, Hancock MA, et al. Development of DNA nanostructures for high-affinity binding to human serum albumin. J Am Chem Soc. 2017;139:7355–7362.
  • Zhao S, Tian R, Wu J, et al. A DNA origami-based aptamer nanoarray for potent and reversible anticoagulation in hemodialysis. Nat Commun. 2021;12:358.
  • Liu J, Song L, Liu S, et al. A DNA-based nanocarrier for efficient gene delivery and combined cancer therapy. Nano Lett. 2018;18:3328–3334.
  • Bujold KE, Hsu JCC, Sleiman HF. Optimized DNA “Nanosuitcases” for encapsulation and conditional release of siRNA. J Am Chem Soc. 2016;138:14030–14038.
  • You M, Peng L, Shao N, et al. DNA “Nano-Claw”: logic-based autonomous cancer targeting and therapy. J Am Chem Soc. 2014;136:1256–1259.
  • Fakih HH, Fakhoury JJ, Bousmail D, et al. Minimalist design of a stimuli-responsive spherical nucleic acid for conditional delivery of oligonucleotide therapeutics. ACS Appl Mater Interfaces. 2019;11:13912–13920.
  • Kim K-R, Kang SJ, Lee AY, et al. Highly tumor-specific DNA nanostructures discovered by in vivo screening of a nucleic acid cage library and their applications in tumor-targeted drug delivery. Biomaterials. 2019;195:1–12.
  • Yamankurt G, Berns EJ, Xue A, et al. Exploration of the nanomedicine-design space with high-throughput screening and machine learning. Nat Biomed Eng. 2019;3:318–327.
  • Veneziano R, Moyer TJ, Stone MB, et al. Role of nanoscale antigen organization on B-cell activation probed using DNA origami. Nat Nanotechnol. 2020;15:716–723.
  • Cremers GAO, Rosier BJHM, and Meijs A, et al. Determinants of Ligand-Functionalized DNA Nanostructure–Cell Interactions. J Am Chem Soc. 2021;143:10131–10142.
  • Leung K, Chakraborty K, Saminathan A, et al. A DNA nanomachine chemically resolves lysosomes in live cells. Nat Nanotechnol. 2019;14:176–183.
  • Samanta D, Ebrahimi SB, Kusmierz CD, et al. Protein spherical nucleic acids for live-cell chemical analysis. J Am Chem Soc. 2020;142:13350–13355.
  • Arulkumaran N, Lanphere C, Gaupp C, et al. DNA nanodevices with selective immune cell interaction and function. ACS Nano. 2021;15:4394–4404.
  • Ghimire C, Wang H, Li H, et al. RNA nanoparticles as rubber for compelling vessel extravasation to enhance tumor targeting and for fast renal excretion to reduce toxicity. ACS Nano. 2020;14:13180–13191.
  • Lacroix A, Sleiman HF. DNA nanostructures: current challenges and opportunities for cellular delivery. ACS Nano. 2021;15:3631–3645.
  • Chandrasekaran AR. Nuclease resistance of DNA nanostructures. Nat Rev Chem. 2021;5:225–239.
  • Kim K-R, Lee T, Kim B-S, et al. Utilizing the bioorthogonal base-pairing system of l-DNA to design ideal DNA nanocarriers for enhanced delivery of nucleic acid cargos. Chem Sci. 2014;5:1533–1537.
  • Ding H, Li J, Chen N, et al. DNA nanostructure-programmed like-charge attraction at the cell-membrane interface. ACS Cent Sci. 2018;4:1344–1351.
  • Gudipati S, Zhang K, Rouge JL. Towards self-transfecting nucleic acid nanostructures for gene regulation. Trends Biotechnol. 2019;37:983–994.
  • Guo S, Li H, Ma M, et al. Size, shape, and sequence-dependent immunogenicity of RNA nanoparticles. Mol Ther. 2017;9:399–408.
  • Zhang Q, Lin S, Shi S, et al. Anti-inflammatory and antioxidative effects of tetrahedral DNA nanostructures via the modulation of macrophage responses. ACS Appl Mater Interfaces. 2018;10:3421–3430.
  • Keller A, Linko V. Challenges and perspectives of DNA nanostructures in biomedicine. Angew Chem. 2020;59:15818–15833.
  • Hill AC, Bartley LE, Schroeder SJ. Prohead RNA: a noncoding viral RNA of novel structure and function. WIREs RNA. 2016;7:428–437.
  • Smith DE, Tans SJ, Smith SB, et al. The bacteriophage straight phi29 portal motor can package DNA against a large internal force. Nature. 2001;413:748–752.
  • Mao H, Saha M, Reyes-Aldrete E, et al. Structural and molecular basis for coordination in a viral DNA packaging motor. Cell Rep. 2016;14:2017–2029.
  • Guo PX, Erickson S, Anderson D. A small viral RNA is required for in vitro packaging of bacteriophage phi 29 DNA. Science. 1987;236:690–694.
  • Gilbert W. Origin of life: the RNA world. Nature. 1986;319:618.
  • Bailey S, Wichitwechkarn J, Johnson D, et al. Phylogenetic analysis and secondary structure of the Bacillus subtilis bacteriophage RNA required for DNA packaging. J Biol Chem. 1990;265:22365–22370.
  • Guo P, Zhang C, Chen C, et al. Inter-RNA interaction of phage φ29 pRNA to form a hexameric complex for viral DNA transportation. Mol Cell. 1998;2:149–155.
  • Gu X, Schroeder SJ. Different sequences show similar quaternary interaction stabilities in prohead viral RNA self-assembly. J Biol Chem. 2011;286:14419–14426.
  • Hao Y, Kieft JS. Diverse self-association properties within a family of phage packaging RNAs. RNA. 2014;20:1759–1774.
  • Hill AC, Schroeder SJ. Thermodynamic stabilities of three-way junction nanomotifs in prohead RNA. RNA. 2017;23:521–529.
  • Hao Y, Kieft JS. Three-way junction conformation dictates self-association of phage packaging RNAs. RNA Biol. 2016;13:635–645.
  • Guo P. The emerging field of RNA nanotechnology. Nat Nanotechnol. 2010;5:833–842.
  • Jasinski D, Haque F, Binzel DW, et al. Advancement of the emerging field of RNA nanotechnology. ACS Nano. 2017;11:1142–1164.
  • Hill AC, Hall J. High-order structures from nucleic acids for biomedical applications. Mater Chem Front. 2020;4:1074–1088.
  • Guo S, Tschammer N, Mohammed S, et al. Specific delivery of therapeutic RNAs to cancer cells via the dimerization mechanism of phi29 motor pRNA. Hum Gene Ther. 2005;16:1097–1109.
  • Khaled A, Guo S, Li F, et al. Controllable self-assembly of nanoparticles for specific delivery of multiple therapeutic molecules to cancer cells using RNA nanotechnology. Nano Lett. 2005;5:1797–1808.
  • Zhang HM, Su Y, Guo S, et al. Targeted delivery of anti-coxsackievirus siRNAs using ligand-conjugated packaging RNAs. Antiviral Res. 2009;83:307–316.
  • Tarapore P, Shu Y, Guo P, et al. Application of phi29 motor pRNA for targeted therapeutic delivery of siRNA silencing metallothionein-IIA and survivin in ovarian cancers. Mol Ther. 2011;19:386–394.
  • Shu D, Shu Y, Haque F, et al. Thermodynamically stable RNA three-way junction for constructing multifunctional nanoparticles for delivery of therapeutics. Nat Nanotechnol. 2011;6:658–667.
  • Abdelmawla S, Guo S, Zhang L, et al. Pharmacological characterization of chemically synthesized monomeric phi29 pRNA nanoparticles for systemic delivery. Mol Ther. 2011;19:1312–1322.
  • Lee TJ, Haque F, Shu D, et al. RNA nanoparticle as a vector for targeted siRNA delivery into glioblastoma mouse model. Oncotarget. 2015;6:14766–14776.
  • Cui D, Zhang C, Liu B, et al. Regression of gastric cancer by systemic injection of RNA nanoparticles carrying both ligand and siRNA. Sci Rep. 2015;5:10726.
  • Zhang Y, Leonard M, Shu Y, et al. Overcoming tamoxifen resistance of human breast cancer by targeted gene silencing using multifunctional pRNA nanoparticles. ACS Nano. 2017;11:335–346.
  • Xu Y, Pang L, Wang H, et al. Specific delivery of delta-5-desaturase siRNA via RNA nanoparticles supplemented with dihomo-γ-linolenic acid for colon cancer suppression. Redox Biol. 2019;21:101085.
  • Setten RL, Rossi JJ, Han S-P. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019;18:421–446.
  • Shen W, De Hoyos CL, Migawa MT, et al. Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index. Nat Biotechnol. 2019;37:640–650.
  • Grimm D, Streetz KL, Jopling CL, et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature. 2006;441:537–541.
  • Wang Y, Vorperian A, Shehabat M, et al. Evaluating the catalytic potential of a general RNA-cleaving FANA enzyme. Chembiochem. 2020;21:1001–1006.
  • Ghidini A, Murtola M, Strömberg R. DNA in Supramolecular Chemistry and Nanotechnology. 2014;158–171.
  • Niittymäki T, Lönnberg H. Artificial ribonucleases. Org Biomol Chem. 2006;4:15–25.
  • Akinori K, Makoto K. Site-selective artificial ribonucleases and their applications. Curr Org Chem. 2007;11:1450–1459.
  • Kaukinen U, Bielecki L, Mikkola S, et al. The cleavage of phosphodiester bonds within small RNA bulges in the presence and absence of metal ion catalysts Journal of the Chemical Society. Perkin Transac. 2001;2:1024–1031.
  • Hüsken D, Goodall G, Blommers MJ, et al. Creating RNA bulges: cleavage of RNA in RNA/DNA duplexes by metal ion catalysis. Biochemistry. 1996;35:16591–16600.
  • Aström H, Williams NH, Strömberg R. Oligonucleotide based artificial nuclease (OBAN) systems. Bulge size dependence and positioning of catalytic group in cleavage of RNA-bulges. Org Biomol Chem. 2003;1:1461–1465.
  • Magda D, Wright M, Crofts S, et al. Metal complex conjugates of antisense DNA which display ribozyme-like activity. J Am Chem Soc. 1997;119:6947–6948.
  • Dogandzhiyski P, Ghidini A, Danneberg F, et al. Studies on tris(2-aminobenzimidazole)-PNA based artificial nucleases: a comparison of two analytical techniques. Bioconjug Chem. 2015;26:2514–2519.
  • Zellmann F, Thomas L, Scheffer U, et al. Site-specific cleavage of RNAs derived from the PIM1 3’-UTR by a metal-free artificial ribonuclease. Molecules. 2019;24:807.
  • Zellmann F, Göbel MW. A trisbenzimidazole phosphoramidite building block enables high-yielding syntheses of RNA-cleaving oligonucleotide conjugates. Molecules. 2020;25:1842.
  • Staroseletz Y, Amirloo B, Williams A, et al. Strict conformational demands of RNA cleavage in bulge-loops created by peptidyl-oligonucleotide conjugates. Nucleic Acids Res. 2020;48:10662–10679.
  • Patutina OA, Miroshnichenko SK, Mironova NL, et al. Catalytic knockdown of miR-21 by artificial ribonuclease: biological performance in tumor model. Front Pharmacol. 2019;10:879.
  • Patutina O, Chiglintseva D, Bichenkova E, et al. Dual miRNases for triple incision of miRNA target: design concept and catalytic performance. Molecules. 2020;25:2459.
  • Murtola M, Wenska M, Stroemberg R. PNAzymes that are artificial RNA restriction enzymes. J Am Chem Soc. 2010;132:8984–8990.
  • Luige O, Murtola M, Ghidini A, et al. Further probing of Cu(2+)-dependent PNAzymes acting as artificial RNA restriction enzymes. Molecules. 2019;24:672.
  • Ghidini A, Murtola M, Stroemberg R. Influence of conjugation and other structural changes on the activity of Cu2+ based PNAzymes. Org Biomol Chem. 2016;14:2768–2773.
  • Murtola M, Virta P, Murtola M, et al. Zinc ion-dependent peptide nucleic acid-based artificial enzyme that cleaves RNA-bulge size and sequence dependence. Molecules. 2017;22:1856.
  • Pettersson M, Crews CM. PROteolysis targeting chimeras (PROTACs) — past, present and future. Drug Discov Today. 2019;31:15–27.
  • Kocaturk NM, Gozuacik D. Crosstalk between mammalian autophagy and the ubiquitin-proteasome system. Front Cell Dev Biol. 2018;6:128.
  • Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16:101–114.
  • Smith BE, Wang SL, Jaime-Figueroa S, et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat Commun. 2019;10:131.
  • Flanagan JJ, Neklesa TK. Targeting nuclear receptors with PROTAC degraders. Mol Cell Endocrinol. 2019;493:110452.
  • Sun X, Gao H, Yang Y, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019;4:64.
  • Burslem GM, Crews CM. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell. 2020;181:102–114.
  • Ghidini A, Cléry A, Halloy F, et al. RNA-PROTACs: degraders of RNA-binding proteins. Angew Chem. 2021;60:3163–3169.
  • Samarasinghe KTG, Jaime-Figueroa S, Burgess M, et al. Targeted degradation of transcription factors by TRAFTACs: transcription factor targeting chimeras. Cell Chem Biol. 2021;28:648–661.
  • Shao J, Yan Y, and Ding D, et al. Destruction of DNA-binding proteins by programmable oligonucleotide PROTAC (O’PROTAC): effective targeting of LEF1 and ERG. Advanced Science. N/a. 2021;8:e2102555–e2102555.
  • Maneiro M, Forte N, Shchepinova MM, et al. Antibody-PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4. ACS Chem Biol. 2020;15:1306–1312.
  • Liu J, Chen H, Ma L, et al. Light-induced control of protein destruction by opto-PROTAC. Sci Adv. 2020;6:eaay5154.
  • Reynders M, Matsuura BS, Bérouti M, et al. PHOTACs enable optical control of protein degradation. Sci Adv. 2020;6:eaay5064.
  • Banik SM, Pedram K, Wisnovsky S, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature. 2020;584:291–297.
  • Gaudet D, Digenio A, Alexander VJ, et al. The APPROACH study: a randomized, double-blind, placebo-controlled, phase 3 study of volanesorsen administered subcutaneously to patients with familial chylomicronemia syndrome (FCS). J Clin Lipidol. 2017;11:814–815.