# Defining the molecular interactions within nanoparticles that enable delivery of long nucleic acids

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $409,859

## Abstract

Project Summary
CRISPR/Cas-based gene editing has ushered in a hopeful era that dreams of new therapies for currently
untreatable genetic diseases. Because mutated proteins are produced in specific cells, there is a critical need to
develop organ- and cell-specific delivery strategies to realize the full potential of genomic medicines. We recently
overcame this challenge through development of the first class of non-viral nanoparticles for tissue-specific
genome editing. Selective ORgan Targeting (SORT) lipid nanoparticles (LNPs) enable targeted intravenous
delivery of nucleic acids and proteins to the lungs, liver, and spleen, plus local delivery to the muscle, brain, and
skin. Tropism is driven by inclusion of SORT molecules, which create tissue-selective 5-component SORT LNPs
that are compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA / sgRNA, and Cas9
ribonucleoprotein (RNP) complexes. In this grant proposal, we Aim to (1) determine the mechanism of SORT,
(2) improve the efficacy and tolerability of liver-, lung-, and spleen-targeting SORT LNPs, and (3) determine the
cell-specific gene editing capabilities of SORT LNPs with the potential for expanded tropism. Results will
determine the fundamental mechanisms and structure-activity relationships (SAR) for non-viral nanoparticle
liver, lung, and spleen tropism. This will ultimately allow targeted and safer CRISPR/Cas gene editing in vivo.
We will determine these factors by adapting a unique class of LNPs, called SORT LNPs, that we developed. We
will employ human cells and genetically engineered mouse models that allow quantification of precise, cell
specific gene editing events. Completion of the proposed studies will (1) Elucidate the fundamental mechanisms
how and why SORT LNPs target extrahepatic tissues, (2) Determine how SORT molecules control efficacy and
tolerability for improved gene editing outcomes, and (3) Determine and control cell-type gene editing specificity
to expand targeted gene editing. Cumulatively, this will open new avenues for CRISPR/Cas-based correction of
genetic diseases by developing efficacious, safe, and clinically translatable nanoparticle carriers.

## Key facts

- **NIH application ID:** 10830404
- **Project number:** 5R01EB025192-07
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Daniel John Siegwart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $409,859
- **Award type:** 5
- **Project period:** 2018-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830404

## Citation

> US National Institutes of Health, RePORTER application 10830404, Defining the molecular interactions within nanoparticles that enable delivery of long nucleic acids (5R01EB025192-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10830404. Licensed CC0.

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