Functional Nanoparticles with a Reducible Tetrasulfide Motif to Upregulate mRNA Translation and Enhance Transfection in Hard‐to‐Transfect Cells

Abstract

Effective messenger RNA( mRNA) transfection in hard-to-transfect cells delivered by vectors is al ong-standing challenge.N ow it is hypothesizedt hat the high intracellular glutathione level is associated with suppressed mRNAt ranslation. This theory leads to an ew design principle of nextgeneration mRNAv ectors:n anoparticles with glutathione depletion chemistry upregulate mRNAt ranslation and enhance transfection, which is beneficial for mRNAd elivery in hard-to-transfect cells in vitro and in vivo.

Emerging Concepts of Nanobiotechnology in mRNA Delivery

“… The contribution of nanostructural parameters to mRNA delivery should be reexamined considering the latest findings. For example, the role of tetrasulfide bonds has been revealed to regulate intracellular biochemical reactions and pathways to upregulate mRNA translation [16] . It has been also reported that tetrasulfide bonds contribute to the GSH‐responsive release of cargo [71] .…”

“…An intracellular biochemistry‐guided design principle of mRNA nanocarriers was proposed: nanomaterials with tetrasulfide groups to deplete GSH‐modulated translation in APCs by reducing glyceraldehyde 3‐phosphate dehydrogenase involved translation suppression and activating mTORC1 for upregulated translation activity and enhanced protein expression efficiency (Figure 2 b). [16] To further modulate translation efficiency, efforts may be made to solve the long‐term GSH depletion problem since tetrasulfide bonds in oxidized GSH can be reduced by glutathione reductase in the cellular metabolism. Furthermore, the exploration of other pathways in mRNA translation and cell‐specific biochemistry to impact the level of eIFs may be integrated into material design as possible strategies to modulate translation and achieve more efficient protein expression.…”

“…b) Nanomaterials with reducible functional groups upregulate mRNA translation. Reproduced with permission [16] Copyright 2020, Wiley‐VCH.…”

Moderne Konzepte der Nanobiotechnologie für mRNA‐Abgabesysteme

“…b) Nanomaterialien mit reduzierbaren funktionellen Gruppen, um die mRNA‐Translation zu verstärken. Reproduziert mit Genehmigung [16] . Copyright 2020, Wiley‐VCH.…”

“…Einige Fragen bleiben jedoch offen; 1) Die Auffassung über den Beitrag nanostruktureller Parameter zur mRNA‐Abgabe sollten unter Berücksichtigung der neuesten Erkenntnisse überprüft werden. Beispielsweise die Rolle der Tetrasulfidbindung bei der Regulierung intrazellulärer biochemischer Reaktionen und Signalwege zur Hochregulierung der mRNA‐Translation [16] . Außerdem wurde gezeigt, dass Tetrasulfidbindungen wesentlich an der GSH‐initiierten Freisetzung von Wirkstoffen beteiligt sind [71] .…”