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Edited by Mark E. Davis, California Institute of Technology, Pasadena, CA, and approved September 20, 2017 (received for review August 11, 2017)
Significance
Clinical evidence has indicated that the systemic spread of endotoxins from septic infection plays a crucial role in the pathogenesis of Gram-negative bacterial sepsis. However, currently there are no effective ways to manage the diverse endotoxins released by different bacterial genus, species, and strain. Herein, we demonstrate the therapeutic potential of a macrophage-like nanoparticle for sepsis control through a powerful two-step neutralization process: endotoxin neutralization in the first step followed by cytokine sequestration in the second step. The biomimetic nanoparticles possess an antigenic exterior identical to macrophage cells, thus inheriting their capability to bind to endotoxins and proinflammatory cytokines. This detoxification strategy may provide a first-in-class treatment option for sepsis and ultimately improve the clinical outcome of patients.
Abstract
Sepsis, resulting from uncontrolled inflammatory responses to bacterial infections, continues to cause high morbidity and mortality worldwide. Currently, effective sepsis treatments are lacking in the clinic, and care remains primarily supportive. Here we report the development of macrophage biomimetic nanoparticles for the management of sepsis. The nanoparticles, made by wrapping polymeric cores with cell membrane derived from macrophages, possess an antigenic exterior the same as the source cells. By acting as macrophage decoys, these nanoparticles bind and neutralize endotoxins that would otherwise trigger immune activation. In addition, these macrophage-like nanoparticles sequester proinflammatory cytokines and inhibit their ability to potentiate the sepsis cascade. In a mouse Escherichia coli bacteremia model, treatment with macrophage mimicking nanoparticles, termed MΦ-NPs, reduced proinflammatory cytokine levels, inhibited bacterial dissemination, and ultimately conferred a significant survival advantage to infected mice. Employing MΦ-NPs as a biomimetic detoxification strategy shows promise for improving patient outcomes, potentially shifting the current paradigm of sepsis management.
Footnotes
↵1S.T., P.A., and T.E. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: vnizet{at}ucsd.edu or zhang{at}ucsd.edu.
Author contributions: S.T., P.A., T.E., R.H.F., W.G., V.N., and L.Z. designed research; S.T., P.A., T.E., Q.Z., J.O., B.T.L., S.Z., R.H.F., and W.G. performed research; S.T., P.A., T.E., Q.Z., J.O., B.T.L., S.Z., R.H.F., W.G., V.N., and L.Z. analyzed data; and S.T., P.A., T.E., R.H.F., W.G., V.N., and L.Z. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Published under the PNAS license.
Biomimetic nanoparticles for sepsis treatment
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