Abstract
Messenger RNAs (mRNAs) were previously shown to have great potential for preventive vaccination against infectious diseases and therapeutic applications in the treatment of cancers and genetic diseases. Delivery systems for mRNAs, including lipid- and polymer-based carriers, are being developed for improving mRNA bioavailability. Among these systems, cell-penetrating peptides (CPPs) of 4–40 amino acids have emerged as powerful tools for mRNA delivery, which were originally developed to deliver membrane-impermeable drugs, peptides, proteins, and nucleic acids to cells and tissues. Various functionalities can be integrated into CPPs by tuning the composition and sequence of natural and non-natural amino acids for mRNA delivery. With the employment of CPPs, improved endosomal escape efficiencies, selective targeting of dendritic cells (DCs), modulation of endosomal pathways for efficient antigen presentation by DCs, and effective mRNA delivery to the lungs by dry powder inhalation have been reported; additionally, they have been found to prolong protein expression by intracellular stabilization of mRNA. This review highlights the distinctive features of CPP-based mRNA delivery systems.
Highlights
After the identification of the Tat peptide, which is derived from the transcription protein of HIV-1, positions 48–60, a variety of protein-derived or designed cell-penetrating peptides (CPPs), which are peptides with cell membrane permeability, have been developed [1,2]
The presence of guanidino groups of Arg residues in CPPs plays a key role in cellular internalization [19,20]; guanidino groups interact with anionic groups on the surface of the cell membrane and promote direct penetration of
DNA, siRNA and antisense oligonucleotide (ASO), demonstrating their huge potential [26], whereas a limited number of reports have addressed the application of CPPs for Messenger RNAs (mRNAs) delivery
Summary
After the identification of the Tat peptide, which is derived from the transcription protein of HIV-1, positions 48–60, a variety of protein-derived or designed cell-penetrating peptides (CPPs), which are peptides with cell membrane permeability, have been developed [1,2]. The presence of guanidino groups of Arg residues in CPPs plays a key role in cellular internalization [19,20]; guanidino groups interact with anionic groups on the surface of the cell membrane and promote direct penetration of CPPs and/or endocytosis [21,22]. Pharmaceutics 2022, 14, 78 example, Arg-rich CPPs) can interact with anionic biomacromolecules, such as DNA and RNA, via electrostatic interactions These properties render CPPs suitable for use as peptide-based vectors. Lipids and polymers have been extensively studied in the context of drug delivery systems (DDS), peptides have distinct features They can be and flexibly designed to possess various functionalities, and the composition of each functional unit (amino acid) of peptides can be precisely controlled. This approach is further expected to expand the options of delivery routes, including oral delivery [25]
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