# Maximizing Therapeutic Accumulation and Retention for Enhanced Cardiac Repair

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $706,718

## Abstract

PROJECT SUMMARY
Ischemic heart disease and its complications are the primary cause of death in industrialized nations. Following
myocardial infarction (MI), ~20-30% of patients develop heart failure, primarily due to loss of contractility through
cardiomyocyte death, inflammation, and formation of scar tissue. Despite intensive research efforts, outcomes
from new regenerative therapies for MI - such as those utilizing stem cells - have been disappointing to date.
However, there is now compelling evidence that mesenchymal stem cells (MSCs) exert their cardio-reparative
effects through the secretion of extracellular vesicles (EVs), whose intrinsic biological properties make them ide-
al candidates for off-the-shelf therapies for ischemic heart disease. Despite a large body of research demon-
strating the tissue-regenerative effects of EVs, their efficient delivery to injured myocardium has been hampered
by three significant challenges: 1) injected EVs tend to diffuse quickly; 2) EVs and other carriers are not retained
long-term in the heart; and 3) local intramyocardial injection is highly invasive. Systemic injection is safer but fails
to deliver a sufficient dosage to the heart. Despite significant efforts to develop targeted delivery methods, there
have been no substantive breakthroughs in addressing these challenges.
The main objective of the proposal is to develop a novel delivery strategy that significantly improves EV
accumulation and substantially prolongs cardiac retention in the injured heart. The specific aims of the study are
as follows: (1) Synthesize and optimize EV formulations and dosing regimens and evaluate their biodistribution,
biocompatibility, toxicity, and immunogenicity using a mouse model of MI. Furthermore, we will assess EV
interactions with cells. (2) Investigate the capability of the optimized EV formulations to facilitate cardiac repair
and explore the underlying mechanisms of action in a mouse model of MI. (3) Assess the effectiveness of EVs
in mediating cardiac repair in a swine model of MI.
These studies will pave the way for developing off-the-shelf EV therapies that can be administered non-
invasively, offering effective treatment options for post-MI care without requiring invasive, open-chest surgery.
This study will establish the critical design parameters of a first-in-class, non-invasive delivery and treatment
strategy achieved through controlled in situ crosslinking. Importantly, our approach can be applied to different
ligands and carrier systems (i.e., micro- and nanoparticles) for enhanced accumulation and retention, not only
at infarct sites, but also other diseases.

## Key facts

- **NIH application ID:** 10905253
- **Project number:** 1R01HL174038-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Juliane Nguyen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $706,718
- **Award type:** 1
- **Project period:** 2024-03-15 → 2028-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905253

## Citation

> US National Institutes of Health, RePORTER application 10905253, Maximizing Therapeutic Accumulation and Retention for Enhanced Cardiac Repair (1R01HL174038-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10905253. Licensed CC0.

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