# RIG-I Activating Nanoparticles for Immunopotentiation

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $78,223

## Abstract

PROJECT SUMMARY
The innate immune system can be pharmacologically programed to elicit desired immunological outcomes.
Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor that has emerged as a promising innate
immune target for immunopotentiation. RIG-I is activated upon recognizing 5’-triphosphorylated, double-
stranded RNA (3pRNA) in the cytosol, which stimulates an antiviral-like inflammatory program that can be
harnessed to treat or prevent a diversity of diseases.
However, the potency and efficacy of 3pRNA has been
limited by major drug delivery barriers, including nuclease degradation, inefficient cellular uptake and cytosolic
delivery, and rapid clearance. To address these challenges, we have developed RIG-I activating nanoparticles
(RANs). RANs are polymer nanoparticles that are engineered to promote the cytosolic delivery of synthetic,
molecularly-defined, and high-affinity stem-loop RNA (SLR) RIG-I agonists recently developed by our team.
The objective of this R01 application is to optimize and advance RANs as a versatile platform for
pharmacological activation of RIG-I. We will accomplish this through the following Specific Aims. First, we will
engineer next-generation RANs with improved properties for systemic administration through optimization of
SLR and polymer charge and hydrophobicity. This approach will leverage combinatorial chemical diversity to
access a new design space for 3pRNA delivery, which we expect will yield next-generation RANs with higher
SLR loading efficiency, reduced cytotoxicity, protection from nuclease degradation, improved stability, and
enhanced immunostimulatory activity. Second, we will establish relationships between RAN properties, innate
immune activation, pharmacokinetics, polymer and SLR biodistribution, and toxicity. These studies are
essential in the preclinical development of new immunotherapeutic modalities and will also yield new insight
into how nanocarriers can be engineered for safe and effective activation of RIG-I. We expect these studies to
yield next-generation RANs that are optimized for systemic administration of SLR therapeutics. Third, while
RANs have broad potential clinical applications, we will evaluate their efficacy as a systemically administered
cancer immunotherapy in poorly immunogenic mouse models of melanoma as a clinically important test case.
We expect to demonstrate that systemic administration of lead-candidate RANs will activate RIG-I in the tumor
microenvironment, resulting in an immunological reprograming of tumor sites that inhibits tumor growth and
synergizes with immune checkpoint inhibitors. Collectively, these studies will position RANs as an enabling
platform for immunopotentiation with potential to address the significant need for new cancer immunotherapies,
antiviral agents, and vaccine adjuvants.

## Key facts

- **NIH application ID:** 10897100
- **Project number:** 5R01EB033822-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Anna Marie Pyle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $78,223
- **Award type:** 5
- **Project period:** 2022-09-30 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897100

## Citation

> US National Institutes of Health, RePORTER application 10897100, RIG-I Activating Nanoparticles for Immunopotentiation (5R01EB033822-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10897100. Licensed CC0.

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