The current landscape of nucleic acid therapeutics

Nature Nanotechnology, Journal Year: 2021, Volume and Issue: 16(6), P. 630 - 643

Published: May 31, 2021

The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, can achieve long-lasting or even curative via gene inhibition, addition, replacement editing. Their clinical translation, however, depends on delivery technologies improve stability, facilitate internalization and increase affinity. Here, we review four platform have enabled translation therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles adeno-associated virus vectors. For each platform, discuss current state-of-the-art approaches, explain rationale behind its development, highlight technological aspects facilitated provide an example a clinically relevant drug. how these enable development cutting-edge drugs, such as tissue-specific bioconjugates, messenger gene-editing therapeutics. This Review provides overview currently used clinic for therapeutics, describing properties, discussing technical advancements led approval, highlighting examples drugs make use technologies.

Language: Английский

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mRNA vaccine for cancer immunotherapy

Molecular Cancer, Journal Year: 2021, Volume and Issue: 20(1)

Published: Feb. 25, 2021

Abstract mRNA vaccines have become a promising platform for cancer immunotherapy. During vaccination, naked or vehicle loaded efficiently express tumor antigens in antigen-presenting cells (APCs), facilitate APC activation and innate/adaptive immune stimulation. vaccine precedes other conventional platforms due to high potency, safe administration, rapid development potentials, cost-effective manufacturing. However, applications been limited by instability, innate immunogenicity, inefficient vivo delivery. Appropriate structure modifications (i.e., codon optimizations, nucleotide modifications, self-amplifying mRNAs, etc.) formulation methods lipid nanoparticles (LNPs), polymers, peptides, investigated overcome these issues. Tuning the administration routes co-delivery of multiple with immunotherapeutic agents (e.g., checkpoint inhibitors) further boosted host anti-tumor immunity increased likelihood cell eradication. With recent U.S. Food Drug Administration (FDA) approvals LNP-loaded prevention COVID-19 therapeutic outcomes achieved several clinical trials against aggressive solid tumors, we envision advancing immunotherapy near future. This review provides detailed overview progress existing challenges future considerations applying immunotherapies.

Language: Английский

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Nanomaterial Delivery Systems for mRNA Vaccines

Vaccines, Journal Year: 2021, Volume and Issue: 9(1), P. 65 - 65

Published: Jan. 19, 2021

The recent success of mRNA vaccines in SARS-CoV-2 clinical trials is part due to the development lipid nanoparticle delivery systems that not only efficiently express mRNA-encoded immunogen after intramuscular injection, but also play roles as adjuvants and vaccine reactogenicity. We present an overview then focus on nanoparticles used current trials. review concludes with analysis determinants performance vaccines.

Language: Английский

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Lipids and Lipid Derivatives for RNA Delivery

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(20), P. 12181 - 12277

Published: July 19, 2021

RNA-based therapeutics have shown great promise in treating a broad spectrum of diseases through various mechanisms including knockdown pathological genes, expression therapeutic proteins, and programmed gene editing. Due to the inherent instability negative-charges RNA molecules, can make most use delivery systems overcome biological barriers release payload into cytosol. Among different types systems, lipid-based particularly lipid nanoparticles (LNPs), been extensively studied due their unique properties, such as simple chemical synthesis components, scalable manufacturing processes LNPs, wide packaging capability. LNPs represent widely used for therapeutics, evidenced by clinical approvals three LNP-RNA formulations, patisiran, BNT162b2, mRNA-1273. This review covers recent advances lipids, derivatives, lipid-derived macromolecules over past several decades. We focus mainly on structures, synthetic routes, characterization, formulation methods, structure–activity relationships. also briefly describe current status representative preclinical studies trials highlight future opportunities challenges.

Language: Английский

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Nanodelivery of nucleic acids

Nature Reviews Methods Primers, Journal Year: 2022, Volume and Issue: 2(1)

Published: April 14, 2022

Language: Английский

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RNA-based therapeutics: an overview and prospectus

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(7)

Published: July 23, 2022

Abstract The growing understanding of RNA functions and their crucial roles in diseases promotes the application various RNAs to selectively function on hitherto “undruggable” proteins, transcripts genes, thus potentially broadening therapeutic targets. Several RNA-based medications have been approved for clinical use, while others are still under investigation or preclinical trials. Various techniques explored promote intracellular trafficking metabolic stability, despite significant challenges developing therapeutics. In this review, mechanisms action, challenges, solutions, therapeutics comprehensively summarized.

Language: Английский

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CRISPR/Cas9 therapeutics: progress and prospects

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 16, 2023

Abstract Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing technology is the ideal tool of future for treating diseases by permanently correcting deleterious base mutations or disrupting disease-causing genes with great precision and efficiency. A variety efficient Cas9 variants derivatives have been developed to cope complex genomic changes that occur during diseases. However, strategies effectively deliver CRISPR system diseased cells in vivo are currently lacking, nonviral vectors target recognition functions may be focus research. Pathological physiological resulting from disease onset expected serve as identifying factors targeted delivery targets gene editing. Diseases both varied complex, choice appropriate methods different important. Meanwhile, there still many potential challenges identified when targeting CRISPR/Cas9 treatment. This paper reviews current developments three aspects, namely, type, vector, characteristics. Additionally, this summarizes successful examples clinical trials finally describes possible problems associated applications.

Language: Английский

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Therapeutic in vivo delivery of gene editing agents

Cell, Journal Year: 2022, Volume and Issue: 185(15), P. 2806 - 2827

Published: July 1, 2022

In vivo gene editing therapies offer the potential to treat root causes of many genetic diseases. Realizing promise therapeutic in requires ability safely and efficiently deliver agents relevant organs tissues vivo. Here, we review current delivery technologies that have been used enable editing, including viral vectors, lipid nanoparticles, virus-like particles. Since no single modality is likely be appropriate for every possible application, compare benefits drawbacks each method highlight opportunities future improvements.

Language: Английский

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Evolution of drug delivery systems: From 1950 to 2020 and beyond

Journal of Controlled Release, Journal Year: 2021, Volume and Issue: 342, P. 53 - 65

Published: Dec. 28, 2021

Language: Английский

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Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration

Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)

Published: Aug. 11, 2021

Abstract Lipid Nanoparticles (LNPs) are used to deliver siRNA and COVID-19 mRNA vaccines. The main factor known determine their delivery efficiency is the pKa of LNP containing an ionizable lipid. Herein, we report a method that can predict from structure We theoretical, NMR, fluorescent-dye binding, electrophoretic mobility methods comprehensively measure protonation both lipid formulated LNP. was 2-3 units higher than primarily due proton solvation energy differences between aqueous medium. exploited these results explain wide range efficiencies in vitro vivo for intramuscular (IM) intravascular (IV) administration different lipids at escalating lipid-to-mRNA ratios In addition, determined more negatively charged LNPs exhibit off-target systemic expression liver following IM administration. This undesirable mRNA-LNP vaccines could be minimized through appropriate design

Language: Английский

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