# Novel Carbon Nanozyme Mechanisms for Traumatic Brain Injury

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2024 · $445,251

## Abstract

Abstract: In the prior funding cycle, we successfully obtained a mechanistic understanding of the chemical basis
for the excellent therapeutic actions in mild traumatic brain injury (TBI) of our carbon nanoparticle (CNP) platform,
poly(ethylene)glycol-hydrophilic carbon clusters (PEG-HCCs). We identified new actions that point to profound
new directions for our CNPs. We: 1) discovered that the HCC's broad redox potential extended their action as
a redox mediator among mitochondrial constituents involved in electron transport, i.e. a nanoparticle enzyme, or
“nanozyme”, and 2) identified a new mechanism by which hemorrhage causes cellular toxicity: rapid and
persistent generation of DNA double strand breaks and robust DNA damage response leading to cellular
“senescence”, in which cells become a nidus for inflammation. While senescence could be prevented by PEG-
HCCs, the cells became sensitized to iron toxicity/ferroptosis. This interaction led us to generate a new CNP,
covalently bonding iron chelator, deferoxamine (DEF). Our results indicate DEF-HCC-PEG effectively
addressed hemin and iron-related injury, senescence and ferroptosis. Given that mitochondrial dysfunction and
hemorrhagic contusion (HC) are associated with poor outcome in TBI, these findings directly indicate the benefit
of pursuing these mechanisms. The identification of key mechanistic features of our CNP platform that facilitate
a mitochondrial site of action and new mechanism of hemorrhage-induced pathology form the basis for this
renewal application. We will incorporate our understanding of the PEG-HCC mechanisms of action to generate
a more immediately translatable CNP utilizing a good manufacturing practice (GMP) starting material, activated
charcoal, and test them in-vivo in a rodent TBI with hemorrhagic contusion (TBI/HC). Our overall hypothesis
is that the mechanisms of action discovered in our prior application will be translatable to GMP starting materials
and will act on both the genomic and mitochondrial damage associated with TBI/HC. Specific Aim 1 will test the
hypothesis that an oxidizing synthesis environment can be optimized to generate GMP-derived starting
materials, PEG-oxidized activated charcoal achieving, the desired characteristics of a CNP nanozyme. Specific
Aim 2 will test the hypothesis that DEF-linked CNP will address hemorrhage-related mitochondrial and genomic
events triggering senescence and resistance to ferroptosis. Specific Aim 3 will administer the CNPs developed
in Aims 1 and 2 to moderate-severe TBI/HC model. Completion of these Aims will yield a more readily
translatable version of our CNP platform building on a growing understanding of the critical features and sites of
action for their nanozyme mechanisms. New therapeutic targets emerging from a more thorough understanding
of pathological mechanisms by which hemorrhage complicates outcome from TBI will guide the design. By
employing GMP starting material, this project can generate breakthrough...

## Key facts

- **NIH application ID:** 10849623
- **Project number:** 5R01NS094535-09
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Muralidhar L Hegde
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $445,251
- **Award type:** 5
- **Project period:** 2015-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849623

## Citation

> US National Institutes of Health, RePORTER application 10849623, Novel Carbon Nanozyme Mechanisms for Traumatic Brain Injury (5R01NS094535-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10849623. Licensed CC0.

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