ncRNAs in Therapeutics: Challenges and Limitations in Nucleic Acid-Based Drug Delivery
Abstract
:1. Introduction
2. Strategies for Fine-Tuning Therapeutic ncRNA Levels by Using Specific Inhibitors or Activators
3. Physiological Barriers Hindering the Clinical Use of Oligonucleotide Therapies
4. Improving the Performance of Nucleic Acid-Based Therapies
4.1. Nucleic Acid Stability Enhancement
4.2. Nanoparticles as Delivery Vehicles: Advantages and Limitations
4.3. Nanoparticles as Delivery Vehicles: Effects of Structure and Composition
5. Future Trends in the Clinical Use of Nucleic Acids for ncRNA Therapy
5.1. Avoiding Immune-Related Adverse Reactions: Nucleic Acid–TLR Interactions
5.2. Improving the Specificity of Targeting Nucleic Acids
5.3. Improving the Delivery of Nucleic Acid-Nanoparticle Systems
5.4. Selecting Appropriate Patients
5.5. Integrating Complex Regulatory Systems
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Chemical Modification | ASOs Improvement | Commercialized or Phase 3 ASOs Drug |
---|---|---|
Nucleobase Modifications | ||
2,6-diaminopurine | Enhance electrostatic interactions with phosphate backbone Enhance target binding affinity and specificity Enhance duplex thermal stability | |
N2-(3-aminopropyl) G | ||
5-methyl C | ||
2-thio T | ||
5-bromo U | ||
Sugar Modifications | ||
2′-Fluoro | Shows duplex stabilizing properties and binding to dsDNA Enhance binding affinity for target RNA sequences Reduce susceptibility toward nuclease degradation | |
2′-MO | ||
(S)-cEt | ||
LNA | Miravirsen | |
2′-MOE | Mipomersen, Nusinersen, Volanesorsen | |
2′-H | Fomivirsen, Mongersen | |
Phosphodiester Linkage & Backbone Modifications | ||
Phosphorotioate (PS) | Improvement of resistance to nuclease cleavage Enhance binding to albumin and heparin proteins Improvement in cellular uptake | |
Thiophosphoroamidate | ||
Phosphorodiamidate morpholino oligomers (PMO) | Eteplirsen, Golodirsen |
SMaterials | Properties | Current 2021 Clinical Trials | Toxical Profiling | References |
---|---|---|---|---|
Inorganic | ||||
Noble metal (Au, Ag, Pt) NPs | Biocompatible, surfaces with multiple cargo, | SP1–SP4 | Cytotoxicity, inflammation, apoptosis | [36,37,38] |
Silica | inmunotherapy | SP5 | Cytotoxicity dose dependent. Oxidative stress, inflammation | [39,40] |
Iron oxide (IONPs and SPIONs), Ferritine | Biocomptability, wide range of sizes and shapes | SP6–SP10 | Cytotoxicity | [41,42] |
Carbon nontubes | ||||
Graphene base nanomaterials | Large surface area, high charge carrier mobility and high stability | SP11–SP14 | Cytotoxicity dose dependent, particle aggregation | [43,44] |
Organic polymers | ||||
Proteins-stabilized NPs | ||||
Albumin | Biocomptability, facilitate endocytosis, great loading efficiency | SP15–SP51 | Low | [45] |
Collagen | Biocompatible, control drug releasing | Non | Low | [46,47] |
Gelatin | Biocompatible, biodegradable | Non | Low | [48] |
CPPs (Cell Penetrating peptides) | Translocate across biological membranes | Non | Low | [49] |
Polysaccharides | ||||
Chitosan | Biocompatible, biodegradable, sustain drug release, low immunogeneity | SP52 | Low | [50] |
Alginate | Biocompatible, low immunogeneity | Non | Low | [51] |
Lipid-based nanoparticles (LNPs) | Enhance internalization and endosomal scape | SP53–SP62 | Disruption of cell membranes and protein aggregation | [52,53,54] |
Covalent complexation with polymers | ||||
PLGA (poly-D,L-lactic-co-glycolic acid) | Biocompatible, biodegradable. | Non | Low | [55] |
PEG (polyethylen glycol) | Increase circulation time and efficiency | Non | Immune-mediated side effects | [56] |
PEI (polyethylenimine) | “Proton sponge” and facilitate endosomal scape. | Non | Oxidative stress and DNA damage. | [57] |
Poly-L-glutamate | Biocompatible | Non | Low | [58,59] |
Dendrimers | Well physical characterized | Non | Oxidative stress and DNA damage. | [60,61] |
Charge-altering releasable transporters (CARTs) | Endosomal scape | Non | No tested | [62] |
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Hueso, M.; Mallén, A.; Suñé-Pou, M.; Aran, J.M.; Suñé-Negre, J.M.; Navarro, E. ncRNAs in Therapeutics: Challenges and Limitations in Nucleic Acid-Based Drug Delivery. Int. J. Mol. Sci. 2021, 22, 11596. https://doi.org/10.3390/ijms222111596
Hueso M, Mallén A, Suñé-Pou M, Aran JM, Suñé-Negre JM, Navarro E. ncRNAs in Therapeutics: Challenges and Limitations in Nucleic Acid-Based Drug Delivery. International Journal of Molecular Sciences. 2021; 22(21):11596. https://doi.org/10.3390/ijms222111596
Chicago/Turabian StyleHueso, Miguel, Adrián Mallén, Marc Suñé-Pou, Josep M. Aran, Josep M. Suñé-Negre, and Estanislao Navarro. 2021. "ncRNAs in Therapeutics: Challenges and Limitations in Nucleic Acid-Based Drug Delivery" International Journal of Molecular Sciences 22, no. 21: 11596. https://doi.org/10.3390/ijms222111596