Mild Innate Immune Activation Overrides Efficient Nanoparticle‐Mediated RNA Delivery

Nov 20, 2019Advanced materials (Deerfield Beach, Fla.)

Mild Immune Response Can Block Effective Delivery of RNA by Nanoparticles

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Abstract

TLR4 activation blocks mRNA translation in all tested cell types while not reducing LNP uptake.

Lipid nanoparticles (LNPs) are being explored for mRNA delivery to treat inflammation.
A novel LNP was identified that delivers mRNA to Kupffer cells at clinical doses, differing from most LNPs that target hepatocytes.
TLR4 activation was found to inhibit mRNA translation despite maintaining LNP uptake.
Inhibition of TLR4 or its downstream protein kinase R enhanced mRNA delivery.
The effects of TLR4 on LNP uptake and translation indicate that inflammatory signaling can affect mRNA delivery outcomes.

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Clinical mRNA delivery remains challenging, in large part because how physiology alters delivery in vivo remains underexplored. For example, mRNA delivered by lipid nanoparticles (LNPs) is being considered to treat inflammation, but whether inflammation itself changes delivery remains understudied. Relationships between immunity, endocytosis, and mRNA translation lead to hypothesize that toll-like receptor 4 (TLR4) activation reduced LNP-mediated mRNA delivery. Therefore, LNP uptake, endosomal escape, and mRNA translation with and without TLR4 activation are quantified. In vivo DNA barcoding is used to discover a novel LNP that delivers mRNA to Kupffer cells at clinical doses; unlike most LNPs, this LNP does not preferentially target hepatocytes. TLR4 activation blocks mRNA translation in all tested cell types, without reducing LNP uptake; inhibiting TLR4 or its downstream effector protein kinase R improved delivery. The discrepant effects of TLR4 on i) LNP uptake and ii) translation suggests TLR4 activation can "override" LNP targeting, even after mRNA is delivered into target cells. Given near-future clinical trials using mRNA to modulate inflammation, this highlights the need to understand inflammatory signaling in on- and off-target cells. More generally, this suggests an LNP which delivers mRNA to one inflammatory disease may not deliver mRNA to another.

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Mild Innate Immune Activation Overrides Efficient Nanoparticle‐Mediated RNA Delivery

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