# Construction of in vivo mRNA delivery systems

> **NIH NIH R35** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $96,459

## Abstract

Project Summary
 Cell-specific drug delivery represents one of the most important research areas in the field of drug delivery.
Particularly, there are formidable challenges for in vivo mRNA delivery. For example, therapeutic window for
current delivery systems is relatively narrow. A large number of cell types cannot be efficiently delivered in vivo.
Biodegradability of the delivery materials remains a concern. In order to address the challenges, the goals of our
research program are: 1) to develop diverse lipid derivatives; 2) to construct mRNA delivery systems; 3) to
examine the delivery efficiency, pharmacokinetics, and safety profile of these systems in animal models. In our
preliminary studies, we developed functionalized lipid-like nanoparticles for in vivo mRNA delivery and base
editing. The lead material was able to produce human factor VIII at a normal physiological level in hemophilia A
mice. The effective base editing was also achieved at low doses in mice. Meanwhile, we constructed vitamin
derived lipid nanoparticles, which enabled adoptive macrophage transfer for eliminating multidrug resistant (MDR)
bacteria in mouse models. Moreover, we showed promising mRNA delivery in other cell types, such as stem
cells and reproductive cells. Additionally, we systematically investigated the untranslated regions (UTRs) of
mRNAs in order to enhance protein production. Through a comprehensive analysis of endogenous gene
expression and de novo design of UTRs, we identified an optimal combination of 5' and 3' UTR, termed as
NASAR, which was significantly more efficient than the tested endogenous UTRs. These preliminary data
provide the scientific foundation to address the delivery challenges of mRNA-based therapeutics. In this proposal,
we propose four directions for mRNA delivery in vivo: (1) to optimize N1,N3,N5-tris(2-aminoethyl)benzene-1,3,5-
tricarboxamide (TT) lipid derivatives for hepatocytes delivery; (2) to investigate vitamin lipid derivatives for
macrophages delivery; (3) to develop glycolipid derivatives for stem cells delivery; (4) to conceive novel lipid
derivatives for reproductive cells delivery. We will prove the concept of cell-specific delivery systems in animal
models. Our research goal is to translate the innovations of this research strategy to develop better mRNA
delivery tools to treat diverse diseases.

## Key facts

- **NIH application ID:** 11034793
- **Project number:** 3R35GM144117-04S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Yizhou Dong
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $96,459
- **Award type:** 3
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11034793

## Citation

> US National Institutes of Health, RePORTER application 11034793, Construction of in vivo mRNA delivery systems (3R35GM144117-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11034793. Licensed CC0.

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