# Vascular Targeting of Nanocarriers for RNA

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $726,234

## Abstract

Clinical approval of Lipid Nano Particles (LNP) for RNA heralded the advent of nanotechnology-
based pharmacotherapy. Yet, RNA delivery to extra-hepatic sites remains a major unmet challenge.
Weissman pioneered modifications of mRNA providing effective translation in diverse cell types, while
Muzykantov introduced “vascular targeting”, nanomedicine strategy for drug delivery to desired areas
in the vasculature. Here we converge these advances to devise nanocarriers targeting RNA to
desired sites of transgene synthesis and therapeutic action. We found that ligands of Inter-Cellular
Adhesion Molecule-1 (ICAM) conjugated to nanocarriers, direct ICAM-LNP (ILNP) to accumulate in
lungs, especially, in the inflamed lungs, with trivial cerebral uptake. In opposite, LNP targeting to
Vascular Cell Adhesion Molecule-1 (VCAM) provides trivial pulmonary uptake of VCAM-LNP (VLNP),
and selective uptake in the inflamed brain, surpassing the benchmarks by orders of magnitude. VLNP
loaded with mRNA encoding endothelial multifunctional anti-thrombotic and anti-inflammatory protein
thrombomodulin (TM) provides transgene synthesis and protective effect in the inflamed CNS
unrivaled by other agents. We will characterize and if needed reiteratively re-engineer targeting
features of this powerful nanotechnology platform, by pursuing the following Specific Aims. Aim 1:
Multi-scale spatiotemporal mapping of vascular targeting of ILNP and VLNP. Using isotope tracing
and real time imaging, in vivo microscopy and flow cytometry, we will define PK/BD, dynamics of LNP
localization and reporter transgene activity in the sites of desirable therapeutic action. Aim 2:
Targeting therapeutic thrombomodulin RNA to lung and brain. We will characterize salient parameters
of TM transgene expression, beneficial and unintended effects of ILNP and VLNP in naive mice and
in mouse models of pulmonary and cerebral inflammation. Aim 3: Translational development of LNP.
We will upgrade LNP to clinically applicable format via site-specific conjugation of small recombinant
ligands. This study will define key specification parameters of a novel nanotechnology platform for
selective delivery of RNA to desirable cells and cellular compartments in brain, lungs and likely other
organs. It will establish proof of principle for a new nanomedicine approach for effective, specific and
safe biological pharmacotherapy of ALI and stroke, with future expansion to other diseases.

## Key facts

- **NIH application ID:** 10093767
- **Project number:** 1R01HL155106-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Vladimir R Muzykantov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $726,234
- **Award type:** 1
- **Project period:** 2021-02-05 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093767

## Citation

> US National Institutes of Health, RePORTER application 10093767, Vascular Targeting of Nanocarriers for RNA (1R01HL155106-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10093767. Licensed CC0.

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