# Ex Vivo Nanoparticle Drug Delivery Targeted to Human Allograft Endothelium

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $642,639

## Abstract

7. Project Summary/Abstract
Peri-transplantation inflammation of solid organ allografts exacerbates acute cell-mediated rejection and
increases late graft loss, primarily caused by chronic rejection. The two most common causes of perioperative
inflammation are ischemia reperfusion injury and, in sensitized recipients, pre-formed donor specific
antibodies, both of which deposit antibody and complement membrane attack complexes (MACs) on graft
endothelial cells (ECs). MAC deposition leads to increased T cell-mediated rejection by inducing expression of
surface proteins on the EC surface that intensify host T cell responses. Two such proteins are ICOS-L (which
in humans engages T cell CD28) and IL-15/IL-15R (which engages T cell IL-2Rc). We hypothesize that
preventing surface expression of these molecules on graft of ECs—i.e “ treating the graft rather than the
recipient”—will reduce early T cell-mediated rejection episodes and late term graft loss and thereby allow
reductions in systemic immunosuppression. In aim 1, we will develop and optimize new antibody-targeted,
degradable solid polyamine co-ester (PACE) nanoparticles (NPs) that can be administered during ex vivo
normothermic machine perfusion and deliver therapeutic siRNAs selectively to ECs that we have shown can
prevent these molecules from being expressed. Solid NPs can slowly release the siRNAs and we will evaluate
efficacy and duration of effects in both cultured cells and perfused human vessel segments. We will then use
these model systems to evaluate changes in allogeneic T cell responses in vitro and, in the case of arteries, in
vivo transplant into human immune system mice. In Aim 2, we will develop antibody-targeted liquid PACE NPs
(polyplexes) to deliver mRNAs encoding Cas enzymes and guide strands that can produce permanent gene
disruption or epigenetic silencing and test these in the same model systems. In Aim 3, we will further develop
approaches to optimize delivery of the antibody-targeted NPs to ECs of human kidneys and hearts that have
been declined for transplantation using established methods of ex vivo normothermic machine perfusion.
These experiments will exploit advances already made by our team, such as fibrinolytic clearing of
fibrinogen/erythrocyte occlusions of graft vasculature to increase access to the whole vasculature and
improved coupling of targeting antibodies using monobody adapters that greatly enhance binding to ECs.
Additionally, we will develop a mouse model of transplant to allow testing of efficacy vs. a fully replete immune
system. The technologies developed in all three aims can be readily adapted for use against other EC targets.

## Key facts

- **NIH application ID:** 10979986
- **Project number:** 1R01AI175206-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JORDAN S POBER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $642,639
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979986

## Citation

> US National Institutes of Health, RePORTER application 10979986, Ex Vivo Nanoparticle Drug Delivery Targeted to Human Allograft Endothelium (1R01AI175206-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10979986. Licensed CC0.

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