Plant-derived nanoparticles as a sepsis therapy - Project Summary Sepsis arises from a life-threatening immune response to infection, causing systemic inflammation, organ failure, and death, yet no FDA-approved therapy currently improves patient survival. With nearly 20% of all global deaths linked to sepsis-related causes, innovative strategies are urgently needed to control inflammation, while maintaining infection control. The long-term goal of this project is to engineer a bio- inspired, tunable lipid nanoparticle (NP)-based immunotherapy capable of mitigating the excessive inflammatory response that drives poor outcomes in sepsis. Our lab recently discovered highly efficacious, anti-inflammatory lipid nanoparticles derived from Lepidium meyenii Walp. (Maca), termed Maca-derived lipid nanoparticles (MDNPs), which significantly reduced systemic IL-6 and TNF levels and rescued 60% of mice from lethal endotoxemia and 40% from polymicrobial sepsis through a novel inflammation-scavenging mechanism via formation of a multimodal protein corona. However, MDNP isolation yields are extremely low (4 mg MDNP per 30 mg plant material), limiting scalability and translational possibilities. To overcome this barrier, we performed lipidomics of MDNPs and prepared bio-inspired triglyceride (Tg)-ceramide (Cer) nanoparticles (TCNPs) that mirror the lipid composition and anti-inflammatory effects of MDNPs, while enabling reproducible, large-scale formulation. Preliminary results show that TCNPs efficiently sequester proinflammatory cytokines in vitro and that dexamethasone (Dex), as a proof-of-concept immunomodulatory drug, could be efficiently encapsulated within TCNP (Dex-TCNP) and the combination was more significantly more effective than either TCNP or Dex alone. In this revised R21 project, we will: (1) optimize the TCNP formulation by modulating lipid compositions and validate cytokine sequestration and multimodal protein corona formation using plasma from healthy and sepsis patients; (2) develop Dex-TCNP as a dual-function therapeutic to enhance drug delivery and amplify anti-inflammatory efficacy; and (3) assess safety, biodistribution, anti-inflammatory, and survival outcomes using the gold-standard cecal ligation and puncture (CLP) model of polymicrobial sepsis. By encapsulating Dex within TCNP, we anticipate achieving potent therapeutic benefit at lower doses, reducing systemic immunosuppression and off-target effects compared to soluble Dex. If successful, this project will establish a novel, bio-inspired nanotherapy that is safe, scalable, and rapidly translatable, offering a powerful complement to existing sepsis treatments and a platform adaptable to other inflammatory diseases.
