Lipid Nanoparticles from L. meyenii Walp Mitigate Sepsis through Multimodal Protein Corona Formation

Sung, J. J.; Shaw, J. R.; Rezende, J. D.; Dharmaraj, S.; Cottingham, A. L.; Weldemariam, M. M.; Jones, J. W.; Kane, M. A.; Pearson, R. M.

doi:10.1101/2024.11.13.623417

bioRxiv · 10.1101/2024.11.13.623417

Lipid Nanoparticles from L. meyenii Walp Mitigate Sepsis through Multimodal Protein Corona Formation

Sung, J. J.·Shaw, J. R.·Rezende, J. D.·Dharmaraj, S.·Cottingham, A. L.·Weldemariam, M. M.·Jones, J. W.·Kane, M. A.·Pearson, R. M.

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Abstract

BackgroundPlant-derived nanoparticles (PDNP) are nano-sized particles isolated from various edible plants that contain bioactive components involved in regulating cellular immune responses against pathogenic intrusion and inflammation. PurposeThis study describes a novel PDNP derived from Lepidium meyenii Walp (maca) that efficiently captures pro-inflammatory cytokines and acute phase proteins in its protein corona to enhance survival in two representative lethal models of sepsis. MethodsLipid nanoparticles were isolated from maca (MDNP) and triacylglycerols and phytoceramides were identified as major constituents using lipidomics. The physicochemical properties of MDNPs were determined, anti-inflammatory effects of MDNP were evaluated using in vitro models and in vivo using endotoxemia and cecal ligation and puncture (CLP) polymicrobial sepsis models. Proteomic analysis of MDNP in healthy or LPS-induced inflammatory plasma was used to determine the composition and inflammatory pathways modulated due to the MDNP protein corona. ResultsIn vitro studies showed that MDNP were non-toxic, reduced macrophage activation, and effectively sequestered pro-inflammatory cytokines to mitigate NF-{kappa}B activity under lipopolysaccharide (LPS) stimulation. In a pre-established LPS-induced endotoxemia model, MDNP-treated mice showed significantly reduced systemic pro-inflammatory cytokines and enhanced survival. Untargeted proteomics and pathway analysis of the MDNP protein corona identified an enrichment in acute phase proteins in MDNP-LPS plasma coronas. MDNP treatment also significantly improved survival in the CLP sepsis model in the absence of antibiotics. ConclusionThis work identified MDNP as an efficient, plant-derived lipid NP that broadly sequesters and neutralizes a compilation of inflammatory mediators in their coronas, offering multimodal therapeutic potential for treating inflammatory diseases.

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Sung, J. J., Shaw, J. R., Rezende, J. D., Dharmaraj, S., Cottingham, A. L., Weldemariam, M. M., Jones, J. W., Kane, M. A., Pearson, R. M.. 2024-11-15. Lipid Nanoparticles from L. meyenii Walp Mitigate Sepsis through Multimodal Protein Corona Formation. https://doi.org/10.1101/2024.11.13.623417

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