Increased PIP3 activity blocks nanoparticle mRNA delivery.

Kalina Paunovska, Alejandro Da Silva Sanchez, Matthew T Foster, David Loughrey, Emmeline L Blanchard, Fatima Z Islam, Zubao Gan, Athanasios Mantalaris, Philip J Santangelo, James E Dahlman

Science advances 2020 Jul

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The biological pathways that affect drug delivery in vivo remain poorly understood. We hypothesized that altering cell metabolism with phosphatidylinositol (3,4,5)-triphosphate (PIP3), a bioactive lipid upstream of the metabolic pathway PI3K (phosphatidylinositol 3-kinase)/AKT/ mTOR (mammalian target of rapamycin) would transiently increase protein translated by nanoparticle-delivered messenger RNA (mRNA) since these pathways increase growth and proliferation. Instead, we found that PIP3 blocked delivery of clinically-relevant lipid nanoparticles (LNPs) across multiple cell types in vitro and in vivo. PIP3-driven reductions in LNP delivery were not caused by toxicity, cell uptake, or endosomal escape. Interestingly, RNA sequencing and metabolomics analyses suggested an increase in basal metabolic rate. Higher transcriptional activity and mitochondrial expansion led us to formulate two competing hypotheses that explain the reductions in LNP-mediated mRNA delivery. First, PIP3 induced consumption of limited cellular resources, "drowning out" exogenously-delivered mRNA. Second, PIP3 triggers a catabolic response that leads to protein degradation and decreased translation. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Citation

Kalina Paunovska, Alejandro Da Silva Sanchez, Matthew T Foster, David Loughrey, Emmeline L Blanchard, Fatima Z Islam, Zubao Gan, Athanasios Mantalaris, Philip J Santangelo, James E Dahlman. Increased PIP3 activity blocks nanoparticle mRNA delivery. Science advances. 2020 Jul;6(30):eaba5672