EGFR-targeted ionizable lipid nanoparticles enhance in vivo mRNA delivery to the placenta.
J Control Release
; 371: 455-469, 2024 Jul.
Article
in En
| MEDLINE
| ID: mdl-38789090
ABSTRACT
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 (15 aEGFR-LNP) mediated a â¼twofold increase in mRNA delivery in murine placentas and a â¼twofold 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Placenta
/
RNA, Messenger
/
Nanoparticles
/
ErbB Receptors
/
Lipids
Limits:
Animals
/
Female
/
Humans
/
Pregnancy
Language:
En
Journal:
J Control Release
Journal subject:
FARMACOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos