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.
Synthetic
polymers are of interest as stable and cost-effective
biomolecule-affinity reagents, since these polymers interact with
target biomolecules both in vitro and in the bloodstream.
However, little has been reported about orally administered polymers
capable of capturing a target molecule and inhibiting its intestinal
absorption. Here, we describe the design of synthetic polymer nanoparticles
(NPs) specifically capturing indole, a major factor exacerbating chronic
kidney disease, in the intestine. N-isopropylacrylamide-based
NPs were prepared with various hydrophobic monomers. The amounts of
indole captured by NPs depended on the structures and feed ratios
of the hydrophobic monomers and the polymer density but not on the
particle size. The combination of hydrophobic and quadrupole interaction
was effective to enhance the affinity and specificity of NPs for indole.
The optimized NPs specifically inhibited intestinal absorption of
orally administered indole in mice. These results showed the potential
of synthetic polymer NPs for inhibiting the intestinal absorption
of a target molecule.
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