EGFR-targeted ionizable lipid nanoparticles enhance in vivo mRNA delivery to the placenta

May 24, 2024Journal of controlled release : official journal of the Controlled Release Society

Targeted lipid nanoparticles improve mRNA delivery to the placenta in living systems

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Abstract

The top-performing EGFR antibody-conjugated lipid nanoparticles (1:5 aEGFR-LNP) achieved a twofold increase in mRNA delivery to murine placentas compared to non-targeted nanoparticles.

Ionizable lipid nanoparticles (LNPs) primarily accumulate in the liver after systemic administration, restricting their use to liver-related conditions.
Targeting LNPs with antibodies may enhance their uptake in specific cell types through receptor-mediated endocytosis.
Preeclampsia and other placental dysfunctions are associated with overexpression of receptors like the epidermal growth factor receptor (EGFR).
The engineered aEGFR-LNP platform was evaluated in both non-pregnant and pregnant mice, showing improved delivery to the placenta.
Increased antibody functionalization on LNPs may facilitate better targeting and delivery of mRNA to EGFR-expressing trophoblasts.

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The full potential of ionizable lipid nanoparticles (LNPs) as an in vivo nucleic acid delivery platform has not yet been realized given that LNPs primarily accumulate in the liver following systemic administration, limiting their success to liver-centric conditions. The engineering of LNPs with antibody targeting moieties can enable extrahepatic tropism by facilitating site-specific LNP tethering and driving preferential LNP uptake into receptor-expressing cell types via receptor-mediated endocytosis. Obstetric conditions stemming from placental dysfunction, such as preeclampsia, are characterized by overexpression of cellular receptors, including the epidermal growth factor receptor (EGFR), making targeted LNP platforms an exciting potential treatment strategy for placental dysfunction during pregnancy. Herein, an EGFR antibody-conjugated LNP (aEGFR-LNP) platform was developed by engineering LNPs with increasing densities of antibody functionalization. aEGFR-LNPs were screened in vitro in immortalized placental trophoblasts and in vivo in non-pregnant and pregnant mice and compared to non-targeted formulations for extrahepatic, antibody-targeted mRNA LNP delivery to the placenta. Our top performing LNP with an intermediate density of antibody functionalization (1:5 aEGFR-LNP) mediated a ∼twofold increase in mRNA delivery in murine placentas and a ∼twofold increase in LNP uptake in EGFR-expressing trophoblasts compared to non-targeted counterparts. These results demonstrate the potential of antibody-conjugated LNPs for achieving extrahepatic tropism, and the ability of aEGFR-LNPs in promoting mRNA delivery to EGFR-expressing cell types in the placenta.

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EGFR-targeted ionizable lipid nanoparticles enhance in vivo mRNA delivery to the placenta

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