# Ionizable Lipid Nanoparticles for Fetal Lung Targeting

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2022 · $51,752

## Abstract

PROJECT SUMMARY
Congenital lung diseases, such as inherited surfactant protein syndromes, cystic fibrosis, and
alpha-1 antitrypsin deficiency, are a significant source of pediatric morbidity and mortality.
Treatment options for neonatal patients with lung disorders that present with respiratory failure
are limited to palliative care or pediatric lung transplant. As such, there is a clear clinical demand
for new therapies that allow for early correction of congenital lung diseases to reduce pediatric
morbidity and mortality. Recent advances in gene editing technologies, such as CRISPR-Cas9
systems, have unlocked the potential to correct pathogenic mutations and thereby treat congenital
disorders at their source. Performing gene editing in utero offers the added benefits of reversing
genetic abnormalities prior to the transition to postnatal life, when pulmonary function becomes
essential, and harnessing normal developmental properties of the fetus for more efficient
correction. Traditionally, viral vectors have been used to study in utero gene therapy in animal
models. Although these studies are encouraging, discovery of alternative, potentially safer,
delivery vehicles will advance the field toward clinical translation. Thus, this proposal aims to
investigate the potential of ionizable lipid nanoparticles (LNPs), a promising non-viral delivery
platform, for nucleic acid delivery to the mouse fetal lung. Fetal lung optimized lipid nanoparticles
(FLO-LNPs) will be generated through a multi-stage optimization scheme. In Aim 1, a diverse
library of 24 ionizable lipid structures will be screened to identify the ionizable lipid that best
delivers mRNA to the fetal lung. In Aim 2, LNP formulations will be optimized using a Design of
Experiments scheme for minimal toxicity and maximal delivery of a CRISPR-Cas9 systems in
mouse precision cut lung slices. In Aim 3, the optimized LNP formulation will be modified via
antibody conjugation and tested for cell-specific targeting in the fetal mouse lung. Ultimately, this
proposal – conducted as an interdisciplinary project between sponsors in the Department of
Bioengineering, Perelman School of Medicine, and Children’s Hospital of Philadelphia at the
University of Pennsylvania – will allow for the development of a novel LNP delivery platform that
can be applied in subsequent work to deliver in utero gene therapies for congenital lung disease.

## Key facts

- **NIH application ID:** 10464943
- **Project number:** 1F30HL162465-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Rohan Palanki
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 1
- **Project period:** 2022-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464943

## Citation

> US National Institutes of Health, RePORTER application 10464943, Ionizable Lipid Nanoparticles for Fetal Lung Targeting (1F30HL162465-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464943. Licensed CC0.

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