# Oral mRNA Nanotherapy for Bleeding Disorder

> **NIH NIH F32** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $49,225

## Abstract

ABSTRACT
Protein replacement therapy has been a cornerstone in treating genetic diseases (e.g., hemophilia) with loss or
reduction of the function of a particular protein, by using recombinant proteins or recombinant engineered
proteins. However, most protein therapeutics have short circulation lives, and thus require frequent invasive
infusion to maintain their therapeutic efficacy. For example, the most common treatment for hemophilia A caused
by a deficiency of blood clotting factor VIII (FVIII) is factor concentrate replacement, which is associated with
burdensome frequent intravenous infusion. To address the unmet medical need of hemophilia, the major
objective of this project is to develop a non-invasive oral mRNA delivery nanoplatform for durable protein
replacement therapy requiring infrequent dosing. Synthetic mRNA has shown enormous potential for biomedical
applications, with mRNA vaccines already clinically approved for COVID-19. Various delivery strategies have
been developed to improve mRNA translation; however, an ongoing challenge of mRNA therapy is managing
the transient efficacy due to its relatively short half-life, and oral mRNA delivery remains elusive. In my previous
work, I have identified a unique poly(zwitterion)-lipid-based micelle platform that can cross the intestinal epithelial
barrier and lead to a very potent oral bioavailability of biomolecules such as insulin. Recently, I have also
discovered a new type of ionizable lipids that can extend the duration of mRNA-mediated protein expression. In
this F32 project, I propose to combine the epithelium-crossing poly(zwitterion)-lipids and the unique ionizable
lipids to develop an innovative mRNA delivery platform for oral, durable replacement therapy of bleeding
disorders. In Aim 1, I will synthesize new poly(zwitterion)-lipids and ionizable lipids and generate a series of new
mRNA lipid nanoparticles (LNPs), and systematically investigate their effects on oral transcytosis and the
durability of protein expression in vitro and in vivo. In Aim 2, we will select the top-performing LNPs for oral
delivery of FVIII mRNA and evaluate the FVIII mRNA nanotherapy in healthy and hemophilia mouse models.
With the successful completion of this project, we expect that the oral durable mRNA delivery strategy will provide
a more effective and robust therapy for hemophilia and other bleeding disorders.

## Key facts

- **NIH application ID:** 11006246
- **Project number:** 5F32HL170556-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Xiangfei Han
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,225
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-03-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11006246

## Citation

> US National Institutes of Health, RePORTER application 11006246, Oral mRNA Nanotherapy for Bleeding Disorder (5F32HL170556-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11006246. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*