# Targeted mRNA therapies treating ARDS

> **NIH NIH K99** · UNIVERSITY OF CHICAGO · 2024 · $110,623

## Abstract

Project Summary/Abstract:
This proposal describes a research and career development plan for Zhengjie Zhou, Ph.D., to transit from a
postdoctoral fellow to an independent investigator position. This proposal will be based on Dr. Zhou’s past
years of multidisciplinary research in nanomedicine and vascular research. Dr. Zhou will be trained at the
University of Chicago by a superb advisory committee of experts who are world-renowned scientists including
Dr. Yun Fang (primary mentor), Dr. Matthew Tirrell (co-mentor), Dr. Jeffrey Hubbell, Dr. Gökhan Mutlu and Dr.
Glenn Randall. This proposal tests the overall hypothesis of fabricated novel lung-targeting liposomal
nanoparticles to deliver therapeutic mRNA in a cell-specific manner for the treatment of acute respiratory
distress syndrome (ARDS), which is the major cause of death for severe influenza and SARS-CoV-2 infection.
Currently, efficient medicines are still lacking for ARDS therapy. ARDS is characterized by the dysfunction of
endothelial cells (ECs), epithelial cells and the following uncontrolled cytokine storm. Based on our recent
research about a vascular cell adhesion molecular-1 (VCAM1) targeting nanotherapeutic study, I rationally
designed and optimized a targeting liposomal nanoparticle that enables robust mRNA delivery in vivo in a cell-
specific manner. Leveraging this mRNA delivery platform, We propose to (i) promote endothelium health by
endothelial cell-specific delivery of KLF2 mRNA to restore KLF2, a transcription factor, that plays a key role in
facilitating endothelial health and vasculature homeostasis. KLF2 was demonstrated significantly reduced in
mice lungs induced by LPS, influenza H1N1, SARS-CoV-2, and COVID-19 patients lungs; (ii) activate
epithelial cells innate immune pathway by epithelium-specific delivery of 2’-5’-oligoadenylate synthetase 1
(OAS1) mRNA to augment epithelium interferon (IFN) response through OAS/RNase L pathway to defense
respiratory viral infection. Our data demonstrated that KLF2 mRNA/VCAM1-targeting liposome targeted the
inflamed mice lungs endothelium and significantly reduced the ARDS induced by H1N1 and SARS-CoV-2. Our
preliminary data demonstrated the OAS1 mRNA/epithelium-targeting liposome targeted the mice inflamed lung
epithelium and significantly reduced the H1N1 replication and lung ARDS. In this project, I will
comprehensively evaluate the therapeutic potency of VCAM1-targeting liposome to restore endothelial KLF2
and lessen ARDS induced by (i) H1N1, or (ii) SARS-CoV-2 in mouse models (Aim 1, K99), and in a clinically
relevant rat ARDS model induced by high-tidal ventilation (HTV) (Aim 2, K99/R00). I will determine how
epithelium-targeted delivery of OAS1 activates the innate immune response and exerts antiviral effects in mice
by OAS1 mRNA/epithelium-targeting liposome and will determine its therapeutic effect to treat respiratory virus
induced ARDS (Aim 3, R00). Successful complete these projects will provide a promising mRNA therapeut...

## Key facts

- **NIH application ID:** 10891734
- **Project number:** 5K99HL166870-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Zhengjie Zhou
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $110,623
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891734

## Citation

> US National Institutes of Health, RePORTER application 10891734, Targeted mRNA therapies treating ARDS (5K99HL166870-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10891734. Licensed CC0.

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