Abstract
Gene therapy offers the possibility to skip, repair, or silence faulty genes or to stimulate the immune system to fight against disease by delivering therapeutic nucleic acids (NAs) to a patient. Compared to other drugs or protein treatments, NA-based therapies have the advantage of being a more universal approach to designing therapies because of the versatility of NA design. NAs (siRNA, pDNA, or mRNA) have great potential for therapeutic applications for an immense number of indications. However, the delivery of these exogenous NAs is still challenging and requires a specific delivery system. In this context, beside other non-viral vectors, cell-penetrating peptides (CPPs) gain more and more interest as delivery systems by forming a variety of nanocomplexes depending on the formulation conditions and the properties of the used CPPs/NAs. In this review, we attempt to cover the most important biophysical and biological aspects of non-viral peptide-based nanoparticles (PBNs) for therapeutic nucleic acid formulations as a delivery system. The most relevant peptides or peptide families forming PBNs in the presence of NAs described since 2015 will be presented. All these PBNs able to deliver NAs in vitro and in vivo have common features, which are characterized by defined formulation conditions in order to obtain PBNs from 60 nm to 150 nm with a homogeneous dispersity (PdI lower than 0.3) and a positive charge between +10 mV and +40 mV.
Highlights
Since 2016, we have observed an acceleration in the development of nucleic acid as therapeutics with the approval of several molecules by the U.S Food and Drug Administration (FDA)
Since the first identification of cell-penetrating peptides (CPPs) as potential new delivery systems, a lot of work has focused on their use in nucleic acid (NA) delivery through a non-covalent strategy consisting of the formation of stable peptide-based nanoparticles (PBNs)
The first contacts during PBN formation result from the electrostatic interactions between the positive charges of the CPP and the negative charges of the NAs
Summary
Since 2016, we have observed an acceleration in the development of nucleic acid as therapeutics with the approval of several molecules by the U.S Food and Drug Administration (FDA). Longer nucleic acids (NAs) such as therapeutic DNAs are mainly used in the form of plasmids (pDNA), which encode specific genes or regulatory sequences for endogenous proteins [9]. In this context, the suppressor gene p53 is the most widely transferred gene in clinical trials due to the fact that it is one of the most frequently mutated genes in different types of cancer [10]. Despite significant advances in different therapeutic NA applications, a major obstacle preventing their widespread usage is the challenge of organ- and tissue-specific delivery To overcome this bottleneck, several strategies have been employed such as the chemical modification of the nucleic acid to improve its ‘drug-likeness’, as well as the use of celltargeting or cell-penetrating moieties for covalent conjugation or nanoparticle formulation.
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