# Novel Peptide/siRNA Nanoparticles for Treatment of Acute Lung Injury

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $539,108

## Abstract

Project Summary/Abstract
 Acute Lung Injury (ALI) and its more severe form Acute Respiratory Distress Syndrome (ARDS) are a
common cause of respiratory failure in critically ill patients. All current therapies for ALI/ARDS rely on
supportive care to improve clinical outcome. No effective drugs have been developed. There is an urgent need
to develop new treatment strategies for ALI/ARDS that are safe, effective, and based on deeper understanding
of the mechanisms involved in ALI pathogenesis. We have discovered that MTOR plays a key role in the
inflammation associated with ALI and that downregulation of MTOR in lung epithelial cells has the potential to
alleviate this inflammation. However, downregulation of MTOR in lung endothelial cells has the opposite effect
and exacerbates inflammation. Thus, to translate these findings into a potential treatment, we must reduce
MTOR levels and activity selectively in the lung epithelium. We have also recently reported the discovery of
disulfide-constrained, cyclic amphipathic peptides (CAPS) that bind to siRNA to form nanocomplexes that can
functionally affect intracellular delivery of siRNA cargo to the lung for protein silencing. We hypothesize that
CAP-siRNA nanoparticles represent an ideal vector for selective delivery of siRNA to lung epithelial cells by
simple aspiration. The overall objective of this proposal is to characterize the mechanism of intracellular siRNA
delivery by CAP-siRNA nanoparticles and to optimize MTOR silencing by these particles toward validation of
their application as a pharmacologic treatment for ALI. We will utilize a cross-disciplinary strategy to
accomplish the stated research objective. The Specific Aims of the proposal are: 1) To characterize the
mechanism of translocation for intracellular delivery of siRNA by our recently reported CAPs. 2) To conduct
structure-activity studies to optimize the efficiency of intracellular siRNA delivery and gene silencing by CAP-
siRNA nanocomplexes. 3) To validate the use of CAP-siRNA nanoparticles for selective knockdown of MTOR
in lung epithelial cells in an in vivo model for ALI. The proposed work requires expertise in both the physical
and biological sciences. The research team draws on expertise in peptide design, lung biology, and gene
therapy. The proposed work will extend existing collaborative relationships between the Nilsson, Dean, and
Rahman groups. Accomplishment of the stated research goal will address significant gaps in understanding of
the disease etiology of ALI, validate the efficacy of MTOR downregulation for treatment of ALI, and provide
peptide/siRNA nanoparticles that facilitate in vivo delivery of MTOR-specific siRNA to the lung. Further, the
proposed CAP agents represent a new class of innovative cell-penetrating peptide motif that is simple and
inexpensive to produce and that does not require covalent attachment of cargo to promote cell entry. It is
anticipated that the proposed CAP-siRNA nanoparticles will be als...

## Key facts

- **NIH application ID:** 9955304
- **Project number:** 5R01HL138538-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** David A Dean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $539,108
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955304

## Citation

> US National Institutes of Health, RePORTER application 9955304, Novel Peptide/siRNA Nanoparticles for Treatment of Acute Lung Injury (5R01HL138538-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9955304. Licensed CC0.

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