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Recent progress in delivering RNA therapeutics to the inside of cells might lead to more success in clinical applications. RNA-based therapeutics, such as small-interfering (siRNAs), microRNAs (miRNAs), antisense oligonucleotides (ASOs), aptamers, synthetic mRNAs and CRISPR–Cas9, have great potential to target a large part of the currently undruggable genes and gene products and to generate entirely new therapeutic paradigms in disease, ranging from cancer to pandemic influenza to Alzheimer's disease. However, for these RNA modalities to reach their full potential, they first need to overcome a billion years of evolutionary defenses that have kept RNAs on the outside of cells from invading the inside of cells. Overcoming the lipid bilayer to deliver RNA into cells has remained the major problem to solve for widespread development of RNA therapeutics, but recent chemistry advances have begun to penetrate this evolutionary armor.

Refinements in the chemistries employed in oligonucleotide therapeutics have galvanized clinical progress. The complex interplay between chemical modifications and integration into sequence architecture is discussed in the context of antisense and small-interfering RNA drugs. After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency are derived primarily from the chemical structure of the oligonucleotide whereas their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design show appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized with a combination of sugar, backbone, nucleobase, and 3′- and 5′-terminal modifications. A portfolio of chemistries can be used to confer drug-like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. One outstanding challenge in oligonucleotide chemical development is the optimization of chemical architectures to ensure long-term safety. There are multiple designs that enable effective targeting of the liver, but a second challenge is to develop architectures that enable robust clinical efficacy in additional tissues.

RNA-based gene therapy requires therapeutic RNA to function inside target cells without eliciting unwanted immune responses. RNA can be ferried into cells using non-viral drug delivery systems, which circumvent the limitations of viral delivery vectors. Here, we review the growing number of RNA therapeutic classes, their molecular mechanisms of action, and the design considerations for their respective delivery platforms. We describe polymer-based, lipid-based, and conjugate-based drug delivery systems, differentiating between those that passively and those that actively target specific cell types. Finally, we describe the path from preclinical drug delivery research to clinical approval, highlighting opportunities to improve the efficiency with which new drug delivery systems are discovered.RNA therapies can be used to manipulate gene expression or produce therapeutic proteins. Here, the authors describe the growing number of RNA therapies and their molecular mechanisms of action. They also discuss the path from preclinical drug delivery research to clinical approval of these drugs.

Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3′-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology. Oligonucleotides targeting mRNA are promising therapeutic agents but suffer from poor bioavailability. Here, the authors develop reduced-charge oligonucleotides with artificial LNA-amide linkages with improved cell uptake and minimal structural deviation to the DNA:RNA duplex.

Antisense technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Nine single-stranded antisense oligonucleotide (ASO) drugs representing four chemical classes, two mechanisms of action and four routes of administration have been approved for commercial use, including the first RNA-targeted drug to be a major commercial success, nusinersen. Although all the approved drugs are for use in patients with rare diseases, many of the ASOs in late- and middle-stage clinical development are intended to treat patients with very common diseases. ASOs in development are showing substantial improvements in potency and performance based on advances in medicinal chemistry, understanding of molecular mechanisms and targeted delivery. Moreover, the ASOs in development include additional mechanisms of action and routes of administration such as aerosol and oral formulations. Here, we describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of ASOs in a wide range of therapeutic applications. We also consider strategic issues such as target selection and provide perspectives on the future of the field.Antisense technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Here, Crooke and colleagues describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of antisense oligonucleotides in a wide range of therapeutic applications.

Recent years have witnessed incredible growth in RNA therapeutics, which has benefited significantly from decades of research on lipid nanoparticles, specifically its key component—the ionizable lipid. This comment discusses the major ionizable lipid types, and provides perspectives for future development. RNA therapeutics have benefited significantly from decades of research on lipid nanoparticles, specifically its key component—the ionizable lipid. This comment discusses the major ionizable lipid types, and provides perspectives for future development.

The RNA interference (RNAi) pathway regulates mRNA stability and translation in nearly all human cells. Small double-stranded RNA molecules can efficiently trigger RNAi silencing of specific genes, but their therapeutic use has faced numerous challenges involving safety and potency. However, August 2018 marked a new era for the field, with the US Food and Drug Administration approving patisiran, the first RNAi-based drug. In this Review, we discuss key advances in the design and development of RNAi drugs leading up to this landmark achievement, the state of the current clinical pipeline and prospects for future advances, including novel RNAi pathway agents utilizing mechanisms beyond post-translational RNAi silencing.The recent approval of the first RNA interference (RNAi)-based therapy has generated considerable excitement in the field. Here, Rossi and colleagues discuss key advances in the design and development of RNAi drugs leading up to this landmark achievement, assess the current clinical pipeline and highlight future opportunities and challenges for RNAi-based therapeutics.

Over the past several decades, messenger RNA (mRNA) vaccines have progressed from a scepticism-inducing idea to clinical reality. In 2020, the COVID-19 pandemic catalysed the most rapid vaccine development in history, with mRNA vaccines at the forefront of those efforts. Although it is now clear that mRNA vaccines can rapidly and safely protect patients from infectious disease, additional research is required to optimize mRNA design, intracellular delivery and applications beyond SARS-CoV-2 prophylaxis. In this Review, we describe the technologies that underlie mRNA vaccines, with an emphasis on lipid nanoparticles and other non-viral delivery vehicles. We also overview the pipeline of mRNA vaccines against various infectious disease pathogens and discuss key questions for the future application of this breakthrough vaccine platform.The COVID-19 pandemic has established mRNA vaccines as a rapid, effective and safe approach for the protection of individuals from infectious disease. Here, Whitehead and colleagues review the principles of mRNA vaccine design, synthesis and delivery, assessing recent progress and key issues in the development of mRNA vaccines for a range of infectious diseases.

More than 25 years after its discovery, the post-transcriptional gene regulation mechanism termed RNAi is now transforming pharmaceutical development, proved by the recent FDA approval of multiple small interfering RNA (siRNA) drugs that target the liver. Synthetic siRNAs that trigger RNAi have the potential to specifically silence virtually any therapeutic target with unprecedented potency and durability. Bringing this innovative class of medicines to patients, however, has been riddled with substantial challenges, with delivery issues at the forefront. Several classes of siRNA drug are under clinical evaluation, but their utility in treating extrahepatic diseases remains limited, demanding continued innovation. In this Review, we discuss principal considerations and future directions in the design of therapeutic siRNAs, with a particular emphasis on chemistry, the application of informatics, delivery strategies and the importance of careful target selection, which together influence therapeutic success.Since the groundbreaking discovery of RNAi more than 25 years ago, several small interfering RNA (siRNA)-based therapies that target the liver have gained approval. This Review discusses principal considerations in siRNA-based drug development, focusing on the medicinal chemistry of siRNA design, the application of informatics, delivery platforms and future directions.