Abstract
Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.
Highlights
Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection, resulting in the dysfunction of multiple organs
Since we previously reported that the inclusion of TBAm and acrylic acid (AAc) in the NIPAm-based hydrogel nanoparticle (HNP) capture positively charged target peptides even in the bloodstream, we selected these functional monomers in this study
A quartz crystal microbalance (QCM) sensor functionalized with histones was used to evaluate the small HNP library for protein binding (Fig. 2c)
Summary
Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. One attempt to improve these involved conjugating histone-capturing synthetic linear copolymers to a lipid NP (a highly biocompatible drug delivery agent), improving the bloodstream circulation time following intravenous injection[32]. These lipid NPs had a low capture capacity and tended to aggregate after histone collection
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