Novel Carbon Nanozyme Mechanisms for Traumatic Brain Injury
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,.........