ABSTRACT Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide and comes with a significant economic burden associated with emergency room visits and hospitalizations. Oxidative stress- mediated secondary injury post-TBI is a considerable risk factor for mortality and long-term impairment. Immediately following TBI, a cascade of biological responses leads to increased production of reactive oxygen species (ROS), a critical mediator of the subsequent pathophysiological events that manifest through lipid peroxidation (LPO), oxidation of proteins and DNA, neuroinflammation, and neurodegeneration. While technological and clinical advancements have improved the outcome for individuals suffering from TBI, there is currently no effective neuroprotective therapy specific for the prevention and treatment of TBI-related secondary injury associated with oxidative stress. Super antioxidants, superoxide dismutase (SOD), and catalase (Cat) have the potential to attenuate the spread of inflammation and brain tissue damage if administered shortly after a TBI. However, the activity of antioxidants is short-lived and rapidly cleared, limiting therapeutic strategies based on exogenous delivery. ProTransit is developing an antioxidant-loaded nanoparticles (NP) delivery system, Pro- NP™, for the treatment of TBI-related secondary injury, as (1) there is currently no effective neuroprotective therapy specific for TBI-related secondary damage; (2) prior attempts have failed clinical translation due to ineffectual drug delivery and retention, and unintended toxicity; and (3) super antioxidants like SOD and Cat are effective but short-lived and rapidly cleared without a robust drug delivery system. The proposed research will address and improve upon current approaches by providing a delivery system, Pro-NP™ that can (1) deliver super antioxidants in a sustained manner, (2) rapidly accumulate and be retained in the damaged brain, and (3) improve TBI recovery. Thus, this proposal will provide a therapeutic strategy for TBI-related secondary brain damage, which is not available through current TBI treatment plans. In contrast with current secondary TBI therapeutic strategies, Protransit’s core patented nanotechnology, Pro-NP™, can deliver biologically active antioxidant enzymes, like SOD and Cat, with sustained release and increased target engagement with the site of injury. With increased accumulation and retention in a damaged brain, antioxidant-loaded Pro-NP™, can exert a protective effect and prevent the spread of biochemical derangements to surrounding healthy brain, potentially providing a significant advantage over other tested therapies. Overall, this Phase I STTR project will determine the feasibility of SOD/Cat-loaded Pro-NP™ to inhibit the development of secondary injury related to TBI. Further, this project will lay the foundation for a Phase II STTR in which we will investigate the pharmacokinetics, biodistribution, and sa...