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bioRxiv · 10.1101/2025.03.06.641448

Nicotinamide-loaded Peptoid Nanotubes for Energy Regeneration in Acute Brain Injury

Du, H.·Trinh, H.·Brandon, O. C.·Zheng, R.·Wang, H.·Corry, K.·Wood, T. R.·Chen, C.-L.·Nance, E.
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Abstract

Acute brain injuries such as perinatal asphyxia, stroke, and traumatic brain injury result in ischemia, oxidative stress, excitotoxicity, and inflammation, leading to a depletion of ATP, the brains cellular energy store. Nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular homeostasis, is crucial for energy regeneration and DNA repair in post-injury recovery. However, the therapeutic benefits of NAD+ and its precursors, such as nicotinamide (NAM), are limited by the complexity of their metabolic pathways and challenges in effective cell-specific intracellular delivery. Therefore, cellular delivery strategies are needed to capture the potential of an NAD+-regenerating therapeutic approach. In this study, we introduce a nanopeptoid delivery strategy to replenish cellular redox state and energy production in the acutely injured brain. By self-assembling peptoids into tubular structures, we created biocompatible NAM-conjugated peptoid nanotubes (NAM-PNTs) that vary in tubular length. NAM-PNTs demonstrated significant therapeutic benefits by enhancing cell viability and replenishing intracellular ATP levels within 24 hours of treatment in oxygen-glucose deprived (OGD) BV-2 cells. In organotypic brain slices, NAM-PNT treatment promoted glial proliferation, reduced pro-inflammatory cytokine levels, and increased anti-inflammatory cytokines after OGD, an ex vivo model of hypoxia-ischemia. A single systemic dose of NAM-PNTs also reduced brain tissue loss and improved neuropathology after hypoxia-ischemia in term-equivalent rats. These findings highlight the strong therapeutic potential of NAM-PNTs for cell-specific targeted delivery and energy restoration in the acutely injured neonatal brain. In the neonatal brain injury field, this is the first demonstration of a novel nanoparticle platform development from first principles design and synthesis to in vitro screening and then demonstration of efficacy in vivo.

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Du, H., Trinh, H., Brandon, O. C., Zheng, R., Wang, H., Corry, K., Wood, T. R., Chen, C.-L., Nance, E.. 2025-03-10. Nicotinamide-loaded Peptoid Nanotubes for Energy Regeneration in Acute Brain Injury. https://doi.org/10.1101/2025.03.06.641448

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