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 a long‐standing challenge. Now it is hypothesized that the high intracellular glutathione level is associated with suppressed mRNA translation. This theory leads to a new design principle of next‐generation mRNA vectors: nanoparticles with glutathione depletion chemistry upregulate mRNA translation and enhance transfection, which is beneficial for mRNA delivery in hard‐to‐transfect cells in vitro and in vivo.

Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

“…[85,165] Silica NPs are well-established vectors capable of delivering mRNA, and typical examples are mesoporous silica nanoparticles (MSNs) which are characterized by facile fabrication properties and large accommodation ability. [166] Wang et al successfully prepared PEI-modified dendritic MSNs (PEI-DMSNs), [167] PEI-modified dendritic mesoporous organosilica nanoparticles (DMONs) containing tetrasulfide (DMONs-PEI), [168] and DMONs with zeolitic imidazolate framework-8 (ZIF-8) partially confined in mesopores (DMONs-ZIF-8) for mRNA delivery and mRNA translation regulation, [169] demonstrating the mRNA delivery potential of silica NP-based hybrid vectors. In another example, Kamegawa et al encapsulated PEI/mRNA complexes in silica shells via bioinspired silicification, and achieved macrophage-targeted mRNA delivery.…”

“…[287] To this end, Wang et al proposed high concentrations of GSH could inhibit intracellular mRNA translation and developed PEI-modified dendritic mesoporous organosilica nanoparticles containing reducible tetrasulfide motif (DMONs-PEI) to enhance mRNA translation in hardto-transfect cells (Figure 13c). [168] The tetrasulfide moieties enabled to deplete intracellular GSH, thereby simultaneously increasing p-RPS6 protein level by activating mTORC1 and reducing GAPDH activity. As a result, this DMONs-PEI platform could function as both mRNA delivery vector and mRNA translation regulator, leading to excellent mRNA transfection efficiency in vitro and in vivo.…”

“…[ 166 ] Wang et al. successfully prepared PEI‐modified dendritic MSNs (PEI‐DMSNs), [ 167 ] PEI‐modified dendritic mesoporous organosilica nanoparticles (DMONs) containing tetrasulfide (DMONs‐PEI), [ 168 ] and DMONs with zeolitic imidazolate framework‐8 (ZIF‐8) partially confined in mesopores (DMONs‐ZIF‐8) for mRNA delivery and mRNA translation regulation, [ 169 ] demonstrating the mRNA delivery potential of silica NP‐based hybrid vectors. In another example, Kamegawa et al.…”

“…Adapted with permission. [ 168 ] Copyright 2019, Wiley‐VCH. d) Scheme illustrating the DMONs‐ZIF‐8 mediated GSH depletion and mammalian target of rapamycin complex 1 (mTORC1) activation for enhancing mRNA translation efficiency.…”

Advanced nanomaterial for prostate cancer theranostics

“…Additionally, the length of the loaded gene is not restricted. There are many non-viral vector types, such as mesoporous silicon ( Wang et al, 2020 ), metal nanoparticles ( Peng et al, 2018 ), linear and dendritic polymers ( Han et al, 2018 ), liposome and its derivatives ( Fenton et al, 2017 ), proteins ( Ping et al, 2017 ), and peptides and their derivatives ( Guan et al, 2019 ). The research on non-viral vectors is not limited to in vitro experiments, and some in vivo experiments have had a very good effect.…”