Poly(lactic acid)-based immunomodulatory nanoparticles promote survival in a polymicrobial mouse model of sepsis

Abstract Sepsis is a life-threatening multifactorial organ dysfunction caused by a dysregulated host response to infection. Despite being recognized as a global health priority, current therapeutic approaches for sepsis have yet to demonstrate significant improvements in patient outcomes. Our group previously demonstrated that cargo-less immunomodulatory nanoparticles (iNPs) could suppress innate immune cell proinflammatory responses and increase survival in an LPS-induced endotoxemia mouse model. In the present work, we examine the impact of poly(lactic acid)-based iNP delivery on survival and comprehensively characterize the host immune response using a clinically relevant and lethal mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP). iNPs, when administered intraperitoneally in combination with broad spectrum antibiotics following CLP surgery, resulted in a significant improvement in disease symptoms and survival compared to CLP + antibiotics only. We also observed that iNP treatment reduced the levels of proinflammatory cytokines in the peritoneal fluid. Analysis of immune cell populations suggested that iNP treatment modulated macrophage, myeloid-derived suppressor cell, and inflammatory monocyte populations both locally and systemically. Our study demonstrates that local administration of iNPs promotes survival through a multimodal immunomodulatory mechanism to improve sepsis outcomes. This research was supported by startup funds from the University of Maryland School of Pharmacy, National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35GM142752, and the Shock Society Faculty Research Award awarded to Ryan Pearson. Nhu Truong is supported by a PhRMA Foundation Pre-Doctoral Fellowship from Washington, DC. This publication was supported by funds through the National Cancer Institute - Cancer Center Support Grant (CCSG) - P30CA134274, and Maryland Department of Health's Cigarette Restitution Fund Program