# Intracellular RNA Nanoparticle Therapeutics to Treat Retinal Neovascularization

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $413,374

## Abstract

ABSTRACT
Diabetic retinopathy is a leading cause of blindness in the industrialized world and has a global prevalence of
an estimated 95 million people (1). Proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME)
originate from persistently elevated glucose levels leading to microvascular ischemia, retinal neovascularization
(RNV), and vascular leakage (2, 3). Antibodies and therapeutics designed to sequester free vascular endothelial
growth factor (VEGF) are the current standard of care (4-8). Due to the short half-life of anti-VEGF therapies,
monthly intravitreal injections are needed to maintain remission (4-7). Repeat injections risk intraocular
inflammation, infection, and ocular hemorrhage (9). An alternative approach is to use RNA interference (RNAi)
to silence the expression of the pathogenic proteins. The recent advancements in siRNA modifications (10) and
FDA approval of the third siRNA therapeutic in as many years demonstrate the renewed potential of RNAi,
though like other anti-VEGF therapies the duration of action is a key limitation. We propose to evaluate the
feasibility of intracellular RNA therapeutics delivered by intravitreal injection of a nanoparticle carrier to
inhibit neovascularization and extend the duration of therapeutic efficacy substantially relative to
current treatments. We recently demonstrated the effectiveness of intravitreally administered fusogenic porous
silicon nanoparticles (F-pSiNPs) for VEGF-siRNA delivery in a DL-alpha-aminoadipic acid (DL-AAA) rabbit
model of RNV. This project aims to rigorously test and optimize this system for extended efficacy. In Aim 1, we
will evaluate two methods of siRNA loading into the nanoparticles: calcium silicate condensation and grafting of
cyclic silanes. These systems will be optimized for loading capacity, encapsulation efficiency, and in vitro release
kinetics. The fusogenic-lipid membrane coating of the F-pSiNP system will be optimized using extrusion and
solvent exchange methods. The candidate formulations will be characterized by spectroscopic, DLS, and Cryo-
EM methods. Cellular uptake and duration of action will be validated in vitro using RT-qPCR and flow cytometry.
The most promising formulations will then be tested by intravitreal injection in Aim 2 using VEGF-siRNA and
Ang-2-siRNA payloads in the DL-AAA model of RNV (11, 12). F-pSiNPs will be given as a single dose and
monitored for 6 months for changes to vascular leakage using fluorescein angiography. These results will then
be benchmarked against commercially available antibody therapeutics aflibercept and faricimab. In Aim 3, F-
pSiNP formulations tested in Aim 2 will be conjugated with pendent surface peptides to test the hypothesis that
selective cellular targeting may dramatically improve efficacy. The targeting and internalization peptide iRGD
will be used for these studies. iRGD is currently in clinical development to improve chemotherapeutic uptake in
tumors, and was selected for its...

## Key facts

- **NIH application ID:** 10914892
- **Project number:** 5R01EY035262-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** William R. Freeman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $413,374
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914892

## Citation

> US National Institutes of Health, RePORTER application 10914892, Intracellular RNA Nanoparticle Therapeutics to Treat Retinal Neovascularization (5R01EY035262-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10914892. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*