Nanodelivery of nucleic acids

Abstract

Gene therapy uses nucleic acids as functional molecules to activate biological treatment for a wide range of diseases, such as cancer 1,2 , cystic fibrosis 3 , heart disease 4 , diabetes 5 , haemophilia and HIV/AIDS 6 . Nucleic acids have been attracting increasing attention owing to the global effort in the human genome elucidation together with recent discoveries such as RNA interference (RNAi) and CRISPR-based genome editing [7][8][9] . Gene therapy uses genetic material to alter the expression of a target gene or to modify the biological properties of living cells for therapeutic needs. In recent years, multiple gene therapy products have been approved by the regulatory agencies for various applications 10 . Perhaps the most relevant example is the authorization of mRNA vaccines to fight the COVID-19 outbreak 11 .Gene therapy can be divided into three main avenues, as detailed in Fig. 1. First is editing mutated genes using CRISPR-Cas technology to cause gain or loss of function 12,13 . Second, upregulating gene expression can be achieved through the insertion of a functional gene copy to be expressed by using molecules such as DNA plasmid (pDNA), minicircle DNA (mcDNA), synthetic mRNA, circular RNA and self-amplifying RNA (saRNA) [14][15][16] . Last is downregulating gene expression using molecules such as small interfering RNA (siRNA), antisense oligonucleotides (ASOs), short hairpin RNA (shRNA) and microRNA (miRNA) 17,18 .Nucleic acids have promising advantages compared with conventional drugs 19 . Unlike the latter, the mechanism of action and high specificity of nucleic acids present a possible therapy route for viral infections, various cancers and undruggable genetic disorders with unmet clinical need. Moreover, theoretically, a single treatment of the genetic payload can achieve a durable and even curative effect 20 . However, delivering nucleic acids to reach their active site inside the cell is challenging owing to their low in vivo stability and rapid host clearance outside cells. Additionally, nucleic acids are poorly permeable through the cellular membrane owing to their negative charge, high molecular weight and hydrophilicity 21 . Nonetheless, few delivery challenges differ between DNA and RNA. For example, the payload and carrier toxicity are of greater concern when delivering RNA molecules usually associated with short-term activity and low retention inside the cell, hence requiring more frequent administration 22 . Alternatively, DNA activity inside the nucleus adds complexity related to low nuclear transport, thus leading to distinguishing design concepts regarding the delivery system compared with RNA molecules 23 . Together with specific challenges relevant to the delivered molecule, the fundamental challenge is to develop tailored systems that can facilitate nucleic acid uptake into target cells. The carrier itself needs to overcome extracellular and intracellular barriers, provide protection from nuclease activity in the bloodstream, enhance and assist with cellular uptake, and promote ...

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