# Liposome Targeting and Triggered Release Driven by Reactive Oxygen Species

> **NIH NIH R15** · UNIVERSITY OF TENNESSEE KNOXVILLE · 2022 · $459,000

## Abstract

Project Summary
Liposomes are supramolecular lipid assemblies that are highly effective at entrapping, delivering,
and enhancing the pharmacokinetic properties of a variety of drug cargo with poor performance
in the absence of a nanocarrier. However, achieving both liposome targeting and spatiotemporal
control over release with high diseased-cell specificity remains a significant challenge that must
be overcome to optimize drug potency and minimize off-target effects. Our approach to surmount
these issues entails the development of “smart” liposomes that respond to overly abundant
reactive oxygen species (ROS) to localize drug delivery to diseased cells. To this end, we have
pioneered the development of ROS-responsive liposomes designed to selectively trigger
therapeutic cargo release in the presence of upregulated ROS. These liposomes harness
synthetic lipid switches in which oxidative cleavage of caging groups leads to lipid decomposition
that destabilizes the liposome membrane to trigger content release. Herein, we propose to
develop next-generation ROS-directed liposomes that will mark a significant technological
advance toward clinical viability.
The proposed work will achieve this goal by developing liposomes that include both activatable
cell-targeting groups and lipid switches that exhibit ROS-responsive properties. First, we will
maximize payload release through the development of advanced immolating lipid structures that
facilitate complete liposome breakdown upon oxidation by ROS (Aim 1). These structures will
exploit programmed intramolecular reactions that degrade ROS-responsive lipid switches into
non-liposome-forming small molecules. Second, we will develop a series of caged cell-penetrating
peptide- (CPP-)lipid conjugates that will activate cell targeting and entry only following ROS
oxidation (Aim 2). These compounds will exploit the exceptional cell delivery properties of CPPs
while solving their primary drawback of poor selectivity. Finally, ROS-responsive lipid switches
and activatable targeting groups, both separately and in combination, will undergo comprehensive
liposome release and cellular delivery evaluations to identify optimal structures and formulations
that maximize therapeutic delivery and diseased-cell specificity (Aim 3). These studies are
expected to culminate in new clinically effective liposomal technology as “smart” carriers
exhibiting diseased cell specificity and optimized release properties.

## Key facts

- **NIH application ID:** 10439073
- **Project number:** 1R15GM146193-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE KNOXVILLE
- **Principal Investigator:** Michael D. Best
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $459,000
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439073

## Citation

> US National Institutes of Health, RePORTER application 10439073, Liposome Targeting and Triggered Release Driven by Reactive Oxygen Species (1R15GM146193-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10439073. Licensed CC0.

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