E-Mail IMAGE: (a) cellular uptake, (b) endosomal escape, (c) GSH depletion contributed by tetrasulfide-induced GSH oxidation and zinc-mediated inhibition of GR and GSSG reduction, (d) GAPDH deactivation, (e) increased MMP, (f) mTORC1... view more Credit: @Science China Press Delivery of genetic molecules such as mRNA into cells is vital with important applications such as vaccine development. Various agents have been developed for mRNA delivery. However, conventional mRNA nanocarriers mainly focus on their physical interaction with mRNA molecules, or protection / delivery of mRNA, such as adjusting physical properties of nanocarriers to control binding with mRNA or cellular uptake. Moreover, effective mRNA delivery in hard-to-transfect APCs remains a challenge. The hard-to-transfect nature in APCs is partly attributed to the suppressed mRNA translation associated with the intrinsic high intracellular glutathione (GSH) level. Thus, tetrasulfide bond bridged DMONs modified with polyethylenimine (PEI) have been reported to oxidize GSH to GSSG (oxidized GSH) to upregulate mRNA translation in APCs. However, the intrinsic cellular regeneration of GSH from GSSG catalyzed by glutathione reductase (GR) could hinder the regulatory efficiency. Besides, the PEI modification to induce endosomal escape raises unwanted cytotoxicity. Therefore, it is highly desired to develop a new mRNA delivery platform with good biocompatibility and long-term bioregulatory capability towards mRNA translation.