The delivery of nucleic acids with transient activity for genetic engineering is a promising methodology with potential applications in the treatment of diseases ranging from cancer and infectious diseases to heritable disorders. Restoring the expression of a missing protein, correcting defective splicing of transcripts and silencing or modulating the expression of genes are powerful approaches that could have substantial benefits in biological research and medicine. Impressive progress in improving gene delivery has been made in the past decade, and several products have reached the market. However, translating the results of in vitro and preclinical studies into functional therapies is hindered by the suboptimal performance of gene delivery vehicles in capturing, protecting and delivering nucleic acid cargoes safely and efficaciously. Chemistry has a key role in the development of innovative synthetic materials to overcome the challenges of producing next-generation gene delivery therapies and protocols. In this Review, we discuss the latest chemical advances in the production of materials for the delivery of nucleic acids to cells and for gene therapy.
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The group of J.M. was partially supported by the Spanish Agencia Estatal de Investigación (AEI) (CTQ2014-59646-R and SAF2017-89890-R), the Xunta de Galicia (ED431G/09, ED431C 2017/25 and 2016-AD031) and the European Regional Development Fund (ERDF). J.M. received a Ramón y Cajal grant (RYC-2013-13784), a European Research Council (ERC) Starting Investigator Grant (DYNAP-677786) and a Young Investigator Grant from the Human Frontier Science Research Program (RGY0066/2017). The authors apologize to all researchers whose work could not be mentioned owing to space constraints.
Spontaneous uptake of single-stranded oligonucleotides that are stabilized with backbone modifications in the absence of any carrier or additive.
An oligonucleotide with a defined 3D structure, which binds specifically to a target molecule, such as a protein, with high affinity.
- Rolling-circle amplification
An enzymatic method to obtain a long single-stranded DNA molecule, which contains many repeats of the target sequence, from a circular DNA template.
- Rolling-circle transcription
An enzymatic method to obtain a long single-stranded RNA molecule, which contains many repeats of the target sequence, from a circular DNA template.
- Chimeric antigen receptor
(CAR). A fusion protein comprising the signalling domain of the T cell receptor and an extracellular antigen-binding domain that is usually derived from an antibody, which promotes T cell activation in the presence of the desired antigen.
- Neonatal Fc receptor
(FcRn). A receptor that is expressed in many tissues and that binds to serum albumin and to some types of antibodies in the slightly acidic conditions in the early endosome, returning them to the cell exterior and preventing their degradation in the late endosome or lysosome.
- Alphavirus replicons
RNA molecules derived from the alphavirus genome, in which genes encoding proteins that are essential for viral replication have been substituted by a gene of interest but can still be replicated and transcribed by the viral RNA polymerase.
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Biomaterials Research (2019)