A nanotrap improves survival in severe sepsis by attenuating hyperinflammation

Changying Shi,Guirong Wang,Matthew Dai,Lili Wang,Xiaojing Wang,Juntao Luo,Dandan Guo,Robert Cooney,Li Chen,Qinghe Meng

doi:10.1038/s41467-020-17153-0

Abstract

Targeting single mediators has failed to reduce the mortality of sepsis. We developed a telodendrimer (TD) nanotrap (NT) to capture various biomolecules via multivalent, hybrid and synergistic interactions. Here, we report that the immobilization of TD-NTs in size-exclusive hydrogel resins simultaneously adsorbs septic molecules, e.g. lipopolysaccharides (LPS), cytokines and damage- or pathogen-associated molecular patterns (DAMPs/PAMPs) from blood with high efficiency (92–99%). Distinct surface charges displayed on the majority of pro-inflammatory cytokines (negative) and anti-inflammatory cytokines (positive) allow for the selective capture via TD NTs with different charge moieties. The efficacy of NT therapies in murine sepsis is both time-dependent and charge-dependent. The combination of the optimized NT therapy with a moderate antibiotic treatment results in a 100% survival in severe septic mice by controlling both infection and hyperinflammation, whereas survival are only 50–60% with the individual therapies. Cytokine analysis, inflammatory gene activation and tissue histopathology strongly support the survival benefits of treatments.

Highlights

Targeting single mediators has failed to reduce the mortality of sepsis
Our TD nanotrap possesses an “octopus-like” flexible dendritic scaffold, which maximizes the conformational entropy in binding with various inflammatory mediators via the ubiquitous and synergistic charge and hydrophobic interactions, e.g., LPS (Fig. 1), cytokines (Fig. 5), and DAMPs/PAMPs (Supplementary Fig. 5)
Conventional adsorption resins are made of hydrophobic polymers for nonspecific adsorption of biomolecules, for example, Cytosorb® for multiple cytokine adsorption

Summary

Introduction

Targeting single mediators has failed to reduce the mortality of sepsis. We developed a telodendrimer (TD) nanotrap (NT) to capture various biomolecules via multivalent, hybrid and synergistic interactions. Therapies developed to neutralize proinflammatory cytokines (e.g., TNF-α17–19 and IL1β20,21) failed to improve sepsis mortality in clinical trials[22] We believe that this is due to the biologic variability of inflammatory response in infected patients, and the fact that multiple inflammatory mediators contribute dynamically to systemic inflammation in sepsis. Based on this concept, we believe that therapies attenuating multiple mediators are promising interventions, which could be used in conjunction with antibiotics and supportive care to improve survival of sepsis. The charge and hydrophobic structures are ubiquitously present in inflammatory mediators, including cytokines, LPS, and DAMP/PAMP molecules[27], like cell-free DNA/RNA, extracellular adenosine triphosphate (ATP), and free heme[28]. Our study demonstrates a 100% survival of severe sepsis in murine models treated with the optimized TD NT in combination with a moderate antibiotic therapy by attenuating both hyperinflammation and infection

Methods

Results

Conclusion