Nanotherapies for sepsis by regulating inflammatory signals and reactive oxygen and nitrogen species: New insight for treating COVID-19

Abstract

SARS-CoV-2 has caused up to 127 million cases of COVID-19. Approximately 5% of COVID-19 patients develop severe illness, and approximately 40% of those with severe illness eventually die, corresponding to more than 2.78 million people. The pathological characteristics of COVID-19 resemble typical sepsis, and severe COVID-19 has been identified as viral sepsis. Progress in sepsis research is important for improving the clinical care of these patients. Recent advances in understanding the pathogenesis of sepsis have led to the view that an uncontrolled inflammatory response and oxidative stress are core factors. However, in the traditional treatment of sepsis, it is difficult to achieve a balance between the inflammation, pathogens (viruses, bacteria, and fungi), and patient tolerance, resulting in high mortality of patients with sepsis. In recent years, nanomaterials mediating reactive oxygen and nitrogen species (RONS) and the inflammatory response have shown previously unattainable therapeutic effects on sepsis. Despite these advantages, RONS and inflammatory response-based nanomaterials have yet to be extensively adopted as sepsis therapy. To the best of our knowledge, no review has yet discussed the pathogenesis of sepsis and the application of nanomaterials. To help bridge this gap, we discuss the pathogenesis of sepsis related to inflammation and the overproduction RONS, which activate pathogen-associated molecular pattern (PAMP)-pattern recognition receptor (PRR) and damage-associated molecular pattern (DAMP)-PRR signaling pathways. We also summarize the application of nanomaterials in the treatment of sepsis. As highlighted here, this strategy could synergistically improve the therapeutic efficacy against both RONS and inflammation in sepsis and may prolong survival. Current challenges and future developments for sepsis treatment are also summarized.

Keywords: COVID-19; Inflammation; Nanotherapy; RONS; Sepsis.

Fig. 1

The scope and focus of this article. The pathogens caused by infection will enter the blood and excessively accumulate in the lesion foci, causing massive inflammation and releasing RONS through activation of the innate immune system. This will lead to blood vessel leakage and further organ dysfunction, and even death. Therefore, blocking activation of the immune system and eliminating the inflammation and RONS is extremely important in treating sepsis. Nanomaterials provide a breakthrough for the treatment of sepsis and can be divided into the following categories: blockade of PRR signaling pathways, nanomaterials for RONS elimination, nanomaterials for eliminating inflammation, and multifunctional nanomedicine.

Fig. 2

Pathological mechanism of sepsis. Under septic conditions, the invasion of immunogens (PAMPs and DAMPs) can over-activate the innate immune system through TLR- and NLR-mediated signaling pathways, causing massive inflammatory cytokine release. These inflammatory cytokines damage the mitochondrial respiratory chain, triggering RONS overproduction. Importantly, because RONS can induce cell apoptosis and reactivate PRR signaling pathways by inducing DAMP formation, it creates a vicious cycle between inflammation and RONS. Thus, inflammation and RONS are the two core factors in the pathological mechanism of sepsis.

Fig. 3

In sepsis, PAMPs/DAMPs cause the overproduction of RONS, which damage immune cells (macrophages and neutrophils) and non-immune cells (endothelial cells). In addition, RONS cause increased permeability of the endothelium, leading to PAMP/DAMP leakage across the vascular wall to other non-infected tissue, damaging normal cells and tissues and causing apoptosis.

Fig. 4

The nanomaterials including the Sheet-like Au nanomaterial (A), Biomimetic nanocomposites (B), Mesoporous silica nanoparticles with PEI(C), and Size-exclusive resin(D) blocking the binding of PAMPs/DAMPs and PRRs, thereby inhibiting the production of inflammation and RONS.

Fig. 5

Some of nanomaterials can eliminate excessive RONS in vivo through mimicking multiple antioxidant enzyme, including Ceria nanozymes(A) and Single-atom catalysts(B). Except that, TMDs nanosheets can effectively scavenge various RONS to treat sepsis(C), as well as nanomaterial can serve as carriers delivering antioxidant to inflammation site(D).

Fig. 6

The balance between pro-inflammation cytokines (TNF-α, IL-3, IL-β, IL-6, IL-12, MIF and INF-γ) and anti-inflammation cytokines (IL-4, IL-10 and TGF-β) are significantly important in sepsis(A). The disordered homeostasis in sepsis can be regulated by nanomaterials through a variety of ways. It can be divided into three categories: (B) nanocarriers(chitosan derivatives, solid lipid nanoparticles, biomimetic nanoparticles) with anti-inflammation drugs can efficiently delivery anti-inflammation drugs (APS and Curcumin) into inflammation site; (C) nanoparticles with anti-inflammation capacity, including Au nanoparticles, SPIO nanoparticles, PLA/PLGA nanoparticles and macrophage/MSC nanovesicles; (D) nanomaterials targeting inflammatory cells (neutrophils and endothelial cells) could decrease the production of inflammation cytokines.

Fig. 7

Multifunctional nanomedicine integrates multiple functions for treating sepsis, including (A) RONS elimination, (B) antibacterial, (C) anti-inflammatory, and (D)targeting.