key: cord-0740153-m2cptovu authors: Chen, Li; Huang, Qiong; Zhao, Tianjiao; Sui, Lihua; Wang, Shuya; Xiao, Zuoxiu; Nan, Yayun; Ai, Kelong title: Nanotherapies for sepsis by regulating inflammatory signals and reactive oxygen and nitrogen species: New insight for treating COVID-19 date: 2021-06-15 journal: Redox Biol DOI: 10.1016/j.redox.2021.102046 sha: 7e273351d7744e158c4063bbe4a1fa45766e531d doc_id: 740153 cord_uid: m2cptovu 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. The scope and focus of this article. The pathogens caused by infection will enter the blood 133 and excessively accumulate in the lesion foci, causing massive inflammation and releasing RONS 134 J o u r n a l P r e -p r o o f through activation of the innate immune system. This will lead to blood vessel leakage and further 135 organ dysfunction, and even death. Therefore, blocking activation of the immune system and 136 eliminating the inflammation and RONS is extremely important in treating sepsis. Nanomaterials 137 provide a breakthrough for the treatment of sepsis and can be divided into the following categories: 138 blockade of PRR signaling pathways, nanomaterials for RONS elimination, nanomaterials for 139 eliminating inflammation, and multifunctional nanomedicine. 140 141 The pathogenesis of sepsis has not been well investigated, but uncontrollable inflammation and 142 excessive RONS are thought to be two key factors that promote the progression of sepsis [24] . 143 Therefore, an in-depth understanding of the mechanisms involved in immune response-induced 144 inflammation and inflammation-induced RONS production is crucial for exploring sepsis 145 pathogenesis and effective means of therapy [25] . In sepsis patients, the activated innate immune 146 system is mediated by PRRs expressed on immune cells (e.g., macrophages and neutrophils) and 147 non-immune cells (e.g., vascular endothelial cells) [9, 26] . PRRs include Toll-like receptors (TLRs), 148 nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible 149 gene-like receptors (RLRs), and C-type lectin receptors (CLRs) [24, 27] . In sepsis, inflammation is 150 mainly mediated by the TLR and NLR signaling pathways [28] (Figure 2 ). 151 The TLR-mediated signaling pathway can be overactivated by PAMPs or DAMPs and lead to 152 the overproduction of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis 153 factor (TNF-α), and IL-6, causing mitochondrial dysfunction, such as an impaired respiratory chain, 154 decreased ATP production, mitochondrial matrix swelling, and collapse of the membrane potential 155 [29] [30] [31] [32] . Eventually, a large amount of O 2 ·is produced by electron leakage at the ubiquinone sites 156 of mitochondrial respiratory chains complex I and complex III [28, [33] [34] [35] . Excessive O 2 ·can be inducible nitric oxide synthase (iNOS) can be over-activated by pro-inflammatory cytokines [38] 160 and cause excessive NO· generation. Importantly, excessive O 2 ·can react with NO· to generate 161 highly reactive ONOO -. Excess RONS can cause cell apoptosis, necrosis, and lysis, which release 162 high quantities of DAMPs [39] . These DAMPs are further recognized by TLRs and prompt 163 inflammatory cytokine and RONS production, forming a vicious circle [24] . NLRs are another 164 important type of receptor that induces excessive inflammation and RONS during sepsis. Under 165 septic conditions, NLRP can form a multiprotein complex or inflammasome, which assembles with 166 the adaptor protein apoptosis-associated speck-like containing a CARD domain (ASC) and 167 caspase-1 [40] [41] [42] . After the NLRP inflammasome is activated, it can promote caspase-1-induced 168 cleavage and maturation of pro-IL-1β and pro-IL-18 to form IL-1β and IL-18, which induce 169 mitochondrial damage, such as TLR signals, and accelerated generation of highly reactive 170 RONS [43] . Importantly, excessive RONS then induce the assembly and activation of NLRP3 171 inflammasomes. Excessive inflammation and RONS cause damage to proteins, lipids, and nucleic acids, which 183 can cause massive immune cell and endothelial cell injury and apoptosis, ultimately leading to an 184 immunosuppressive state in the body [28, 44] . Excessive inflammation and RONS also impair the 185 activity of non-immune cells, such as endothelial cells [45] . The endothelium is a selective 186 permeable barrier between the vascular wall and blood flow and one of the first protective barriers 187 against external invasion [46] . In sepsis, excessive inflammation and RONS will increase endothelial cell permeability, leading to the leakage of fluids and proteins through the vascular wall, Sepsis is dominantly caused by an imbalance of host to infection, which is mainly induced by 208 bacteria, viral, fungus [48] . [57] . Thus, it is an effective approach to target signaling pathways with specific based on gold nanoclusters (SAuNCs) coated with a layer of short-chain alkanes ( Figure 4A ) [58] . The short-chain alkanes on the surface of the SAuNC can bind to LPS and cause the aggregation pathways is more effective than blocking a single pathway [73] . In terms of molecular structure, Under physiological conditions, redox homeostasis is preserved in the body by redox buffering systems. The system's delicate balance is preserved by antioxidant enzymes containing SOD, 321 catalase, and glutathione peroxidase (GPx) [28] . In sepsis, excessive RONS far exceed the 322 scavenging ability of antioxidant enzymes in vivo and can cause oxidative stress in the body, which 323 in turn produces more RONS [30, 75, 76] . Therefore, it is necessary to rely on the administration of 324 exogenous antioxidants to maintain the body's redox balance. However, traditional antioxidants 325 present many shortcomings, such as severe side effects, rapid clearance, and low stability and [87] . Therefore, ceria nanozyme can be applied in the treatment of sepsis by eliminating ROS (Figure 5A ). Selvaraj et al. anti-inflammatory activities [89, 90] . However, the application of ceria nanozyme is limited by its potential toxicity and low In addition to nanozymes, RONS nanoscavengers also play important roles in antioxidant therapy 403 by directly reacting with excessive RONS [95] . Recently, two-dimensional (2D) transition-metal 404 dichalcogenide (TMD) nanosheets were proposed as novel RONS scavengers that can be applied in 405 the treatment of sepsis [96] . Compared to conventional antioxidants, 2D-TMD nanosheets can 406 effectively remove various RONS with low cytotoxicity, good biocompatibility, structural stability, 407 and durability of action [97, 98] . Sepsis is a disease closely related to oxidative stress. In theory, treatment of sepsis with 420 antioxidants is a promising strategy. However, the therapeutic potential of many antioxidants (e.g., natural antioxidants, endogenous antioxidants, synthetic organic antioxidants) is restricted by factors such as solubility, stability, and low bioavailability (e.g., poor gastrointestinal absorption). (Figure 5D ) [101] . PPS undergoes an oxidative conversion from hydrophobic to hydrophilic. As a result, the nanoparticles become swollen and disassemble when exposed to H 2 O 2, and then Inflammation imbalance is the most critical mechanism responsible for the onset and progression of 441 sepsis, which underlies the whole pathological process [70] . The inflammation response in sepsis incorporating proteins derived from the plasma membrane into nanoparticles [106, [111] [112] [113] . Biomimetic nanoparticles can effectively avoid being cleared by the reticuloendothelial system and 492 circulate in the body longer than ordinary nanomaterials [111] [112] [113] [114] . broadly classified into two groups: M1 macrophages that secrete pro-inflammatory cytokines, and 500 M2 macrophages that secrete anti-inflammatory cytokines [116, 117] . AuNPs improve the survival 501 rate of septic mice by alleviating systemic inflammation [115] . Similarly, Xu et al. showed that 502 SPIONs can enhance secretion of anti-inflammatory cytokine IL-10 by activating autophagy in 503 macrophages, alleviating inflammation in septic mice [118] . Therefore, the application of these The inflammatory response of sepsis is a very complex process that involves the innate immune 521 system, the adaptive immune system, and endothelial system. In the innate immune system, 522 phagocytosis-related cells, such as macrophages and neutrophils, play critical roles in removing 523 pathogens [123] . However, inflammation can disrupt the neutrophil death program (apoptosis) to 524 prolong neutrophils longevity, and the number of neutrophils rapidly increases in sepsis [102] . These neutrophils secrete massive amounts of inflammatory cytokines, which in turn cause 526 neutrophil migration dysfunction. Subsequently, the deleterious accumulation of these 527 dysfunctional neutrophils could cause tissue injury within remote vital organs [123, 124] . Therefore, anti-inflammatory, anti-coagulant, and anti-adhesive states [127] . However, excessive inflammation 540 and RONS could damage endothelial cells, leading to their dysfunction and structural damage under septic conditions [47] . Therefore, inhibiting the inflammatory response of endothelial cells is 542 also a crucial aspect of treating sepsis ( Figure 6D) . Notably, recombinant activated protein C 543 (APC), a component of the natural anticoagulant system, has been applied in the treatment of sepsis 544 due to its potent anti-inflammatory activity for endothelial cells [128, 129] , but the severe bleeding The course of sepsis is often the result of a combination of several factors that influence and 566 interact with one another [11, 133] . Therefore, therapies that only intervene with a single factor will 567 compromise therapeutic effects and cannot effectively treat sepsis. Multifunctional nanomedicine 568 can simultaneously deliver multiple therapeutic agents to interfere with multiple pathogenic factors. Thus, multifunctional nanomedicines to treat sepsis have great advantages and prospects for 570 application (Figure 7) . The vicious circle between inflammation and RONS is a critical factor in the pathogenesis of 576 sepsis [28, 134] . Therefore, simultaneous intervention for inflammation and RONS can be an increase systolic blood pressure, and decrease the murine sepsis score (MSS) in septic mice. Overall, SQAd/VitE NPs provide an effective treatment by blocking the pathological cross-talk 597 between oxidative stress and inflammation. Inflammation is the body's natural response to harmful stimuli [136] , but excessive 599 inflammation leads to dysfunction of the host's immune system [137, 138] . Although and DNA damage through acute intravenous administration [145] . There are also reports that 666 titanium dioxide nanoparticles and others nanoparticles are harmful to kidney [146, 147] . Tungsten 667 trioxide nanoparticles and iron oxide nanoparticles can cause liver toxicity in mice [148, 149] . There are many nanoparticles that can also damage the liver [150, 151] . In general, the toxicity and 669 therapeutic effects of nanomaterials are generally dose-dependent. Therefore, the dosage of 670 nanomaterials needs to be carefully selected, and a balance should be reached between the toxicity 671 of nanomaterials and the therapeutic effect. In addition, some researchers believe that concerns about the toxicity of nanomedicine have been exaggerated. It does not mean it is dangerous just 673 because a material is nanoscale. In fact, nanoparticles were existed since the birth of the earth, for 674 example, the nanoparticles were naturally existing in the organism, volcanic ash and ocean 675 spray [152] . Moreover, human activity also produced excessive nanomaterials, such as dust and 676 fume. The current nanomaterials targeting for sepsis treatment mainly derived from the passive J o u r n a l P r e -p r o o f As the world continues to experience the effects of COVID-19, we present the latest advances in nanotherapy for sepsis with the aim of contributing to the treatment of this new, severe coronary disease. Here, we summarized recent advances in understanding the pathological mechanism of sepsis and the potential application of nanomedicines for sepsis treatment. Nanotherapies are promising for sepsis treatment, and the nanomaterials mediating RONS and the inflammatory response have achieved previously unattainable therapeutic effects in sepsis. Despite the rapid advances, further optimization of nanomaterials is urgently needed to treat sepsis in a more comprehensive and effective manner. First, the pathogenesis of sepsis is the result of multiple factors, so single therapeutic agents are currently insufficient. However, the proposed multifunctional therapy is still in its infancy. Developing appropriate nanoparticles to meet the multifunctional requirements for sepsis treatment has become a crucial research focus. Second, ideal nanomaterials should not only have low toxicity and excellent bioavailability and stability, but they should also be able to easily target infectious tissues. The physical and chemical properties of nanomaterials are closely related to the particle size, surface charge, and surface modification [22] . Therefore, it is necessary to continuously optimize the preparation of nanoparticles. Third, inflammation in sepsis is caused primarily by the activation of TLRs and the NLR-mediated signaling pathway. However, recent studies on nanomaterials have focused mainly on blocking activation of the TLR signaling pathway. Yet, blocking the NLR-mediated signaling pathway can also inhibit activation of the innate immune system. Therefore, it is promising to design nanomaterials that block the NLR-mediated signaling pathway or both the TLR and NLR-mediated J o u r n a l P r e -p r o o f signaling pathways for the treatment of sepsis. Finally, many bacteria develop multidrug resistance and develop immune escape mechanisms in response to the host immune response and the abuse of antibiotic therapy [161] [162] [163] . Particularly in the immunosuppressive stage of late sepsis, there is a very complicated and contradictory relationship between regulating the level of inflammation and killing pathogens. Currently, most nanomaterials are focused on the first stage of sepsis (excessive activation of the inflammatory response) and are rarely involved in the late stage of sepsis. Nanomedicines should have great advantages and prospects through carefully designed multifunctional nanomaterials to balance the complex relationship between the late-stage regulation of inflammation and the elimination of pathogens. The development of new and effective nanomedicines for therapies based on inflammation and RONS will achieve a significant breakthrough in the treatment of sepsis [164, 165] . The efficacy of nanomaterials therapy should be assessed in clinical trials. 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