A clear understanding of the pathophysiology of sepsis and potential drug targets is critical for developing new effective sepsis diagnostic and therapeutic tools. This section will discuss the pathophysiological background of sepsis, including the inflammatory pathways triggered by invading microorganisms and the consequences of that on the structure and function of body organs. The current trends in sepsis diagnosis and management and potential drug targets for sepsis management will also be discussed, accompanied by their challenges. Finally, the physicochemical and biological properties that make peptides a potential component of nanotools for sepsis diagnosis and management are covered.

Pathophysiology of sepsis

Sepsis is a medical emergency and a life-threatening condition associated with a global disease burden [52]. Despite all experimental and clinical research efforts, sepsis remains one of the leading causes of morbidity and mortality in critically ill patients [53]. In the Third International Consensus (Sepsis-3), sepsis is defined as "organ dysfunction caused by a dysregulated host response to infection", highlighting for the first time the critical role of immune responses in the establishment of the illness [7]. After the invasion of microorganisms into the body, an immune response is triggered to fight off the invading microorganisms. This causes inflammation, a normal and necessary response to promptly identify, eradicate, and keep the infection localized [54]. However, as shown in Fig. 1, the immune response is exaggerated during sepsis, resulting in collateral damage and death of host cells and tissues, compromising both the affected and distant organs and leading to functional abnormalities and life-threatening multiorgan failure [55]. The pathophysiology of sepsis is generally defined as an early hyperinflammatory state that lasts many days, followed by a longer immunosuppressive state [56]. These two stages are connected with higher mortality, with the highest death rate in the early phase attributable to an enormous inflammatory response (cytokine storm) [14].

Fig. 1

Immune responses in sepsis owing to infection. Illustration of converting to sepsis from infection. Immune cells activation results in the overproduction of inflammatory mediators that induce detrimental changes in cells and tissues, leading to multiorgan dysfunction and failure (SOFA: sequential organ failure assessment; EWS: early warning score; iNOS: inducible nitric oxide synthase; ARDS: acute respiratory distress syndrome) (Adopted with permission from [55]

The over-released inflammatory mediators during the cytokine storms lead to significant damage to the endothelium and disruption of it is barrier function, vasodilation, activation of coagulation pathways, platelet aggregation and adhesion, and mitochondrial dysfunction [57, 58]. Overall, the dysregulated inflammatory-immune responses and their consequences mentioned above eventually lead to the formation of microvascular thrombi, hypotension, impaired cellular functions, local perfusion defects, tissue hypoxia, and progressive tissue damage, which finally cause refractory shock and multiorgan failure [59,60,61,62]. Cardiovascular Dysfunction, acute lung injury and acute respiratory distress syndrome, acute kidney injury, hepatic dysfunction, and CNS dysfunction and encephalopathy are well-known complications of sepsis, and their underlying mechanisms are reported in the literature [63,64,65,66,67,68]. These alterations and dysfunctions in the tissues and organs collectively contribute to much of the morbidity and mortality of sepsis [69].

Although the advancements in therapeutic approaches have enhanced the survival rate in the early phase of the exaggerated inflammatory response, current patterns in sepsis indicate that mortality arises during the subsequent stage of a compensatory immunosuppressive response when there is a shift toward an overall anti-inflammatory milieu [56, 70]. This post-sepsis immune paralysis involves various quantitative and functional defects of immune cells as a result of uncontrolled apoptosis of lymphocytes and decreased immunoglobulin production, which is linked to an increased susceptibility to secondary infections and organ injury and/or failure [14, 60, 71, 72]. Immunosuppression can last months after the septic event and is associated with increased mortality [73, 74]. The detailed sepsis pathophysiology and different involved pathways have been widely discussed in the literature, and readers are referred to them for more details [55, 67, 69, 73, 75,76,77].

Sepsis diagnosis and management

Sepsis is considered a medical emergency that, if not diagnosed in its early stages, will result in a poor prognosis with increased morbidity and mortality [78]. The current diagnosis of sepsis relies on clinical evaluation, blood or urine cultures, and detection of inflammatory response biomarkers such as C-reactive protein (CRP), procalcitonin (PCT), and interleukin 6 (IL-6) [19]. However, the currently used biomarkers are not specific, and none have proven to be a specific sepsis indicator [79]. Moreover, the microbial cultures take a long time, and results may come out after 72 hours, making rapid sepsis diagnosis difficult [80]. Starting sepsis management as early as possible is critical to avoid complications and multiorgan failure [81]. As the current diagnostic tools for sepsis have such a delay, the empirical administration of intravenous broad-spectrum antibiotics is a usual initial intervention together with other additional therapies (e.g., anti-inflammatory (corticosteroids) and venous thromboembolism prophylactics) and measures for ventilation and hemodynamic stabilization (e.g., oxygen, albumin, and vasopressors administration and fluid resuscitation) [82]. However, the empirical use of broad-spectrum antibiotics with the uncertainty of diagnosis results and difficulties in differentiating infectious sepsis from noninfectious inflammations [83] will result in unwanted side effects for the already stressed patient and increased risk of antimicrobial resistance development [81, 84]. Putting all these challenges together raises the urgent need for new and specific sepsis diagnostics and management approaches.

Drug targets in sepsis

As mentioned above, treating sepsis involves a combination of antibiotics to fight the underlying infection and supportive care to address the systemic inflammation and organ dysfunction that can occur because of the condition [85]. One of the key challenges in treating sepsis is identifying effective drug targets that can help reducing inflammation and tissue damage [86]. Besides targeting the invading microorganisms with antibiotics, several drug targets have been identified and studied in sepsis management [87, 88]. One of the main drug targets in sepsis is the inhibition of inflammatory mediators that play a critical role in developing sepsis, including cytokines, chemokines, and other inflammatory signaling molecules [89]. Drugs that target these inflammatory mediators have been developed and tested as potential treatments for sepsis [90]. For example, monoclonal antibodies that neutralize TNF-α, such as infliximab and etanercept, have been shown to improve outcomes in patients with sepsis [91]. Similarly, drugs that inhibit the activity of IL-1 (e.g., IL-1 receptor antagonist), IL-6, and IL-8 have also been shown to improve outcomes in patients with sepsis [92].

The coagulation cascade is another critical therapeutic target in sepsis [93]. As sepsis is associated with a hypercoagulable state, targeting the coagulation process with drugs such as anticoagulants or clotting factor inhibitors can prevent micro-clots formation and improve outcomes in sepsis [94]. Drugs that target the coagulation cascade, such as activated protein C (APC) and thrombin inhibitors, have been studied as sepsis therapies and demonstrated to enhance sepsis outcomes [88, 95]. Furthermore, the endothelial cells that line blood vessels play a crucial role in the body's reaction to inflammation and infection [96]. As a result, targeting the endothelium to manage sepsis is an active area of research [96]. In sepsis, the dysfunction of these cells can lead to increased permeability of blood vessels and decreased blood flow and so leakage of fluid and plasma protein into the tissues, resulting in hypotension and organ dysfunction [97]. One of the key pathways activated in the endothelium during sepsis is the nitric oxide (NO) pathway, leading to excessive vasodilation and decreased blood pressure [98]. Drugs that target the NO pathway, such as nitric oxide synthase inhibitors, have been investigated as potential treatments for sepsis [99]. Another promising strategy is the use of drugs that can improve endothelial function and reduce inflammation [100]. For example, endothelial protective agents, such as statins, have been shown to reduce inflammation and improve blood flow in sepsis [101]. In addition, new approaches, such as using extracellular vesicles as drug carriers for targeting the endothelium, are also being explored [102].

The complement system, a part of the immune system that helps identify and eliminate foreign invaders such as bacteria and viruses, is also one of the potential drug targets for sepsis management [103]. In sepsis, the complement system is overactivated, which can lead to inflammation and tissue damage [104]. As a result, targeting the complement system has been investigated for managing sepsis [105]. One approach to target the complement system in sepsis management is using complement inhibitors, which are drugs that block the activation of the complement system [106]. For example, eculizumab, a monoclonal antibody that targets the complement protein C5, has been shown to reduce the incidence of death and organ failure in patients with sepsis caused by meningococcal infections [107].

Bacterial toxins such as lipopolysaccharides (LPS) from Gram-negative bacteria, exotoxins from Gram-positive bacteria, and superantigens from both Gram-positive and Gram-negative bacteria are also potential targets in the management of sepsis [108]. Bacterial toxins can contribute to the development of sepsis by triggering the release of inflammatory cytokines and damaging vital organs and tissue, leading to septic shock and death [109]. Inhibiting the production or activity of these toxins can prevent toxicity and improve outcomes in sepsis management [108]. Various strategies are being studied, such as blocking toxins' binding to host cells, inhibiting their production, or neutralizing them using toxin-binding proteins or immunoglobulins [90, 110]. Even though developing therapies that target bacterial toxins is a promising area of research for treating sepsis, more research needs to be done to understand how these drugs work fully and if they are safe to use in clinical settings.

Overall, managing sepsis remains a complex and challenging task, and there is currently no single drug that can effectively address all the different pathways and processes involved in the condition. Further research is needed to identify additional drug targets and to develop more specific and effective medicines for sepsis.

Potential of peptides for use in sepsis

Several drugs have failed in the treatment of sepsis. However, continued research and improved understanding of sepsis pathophysiology, including the complex interactions between inflammatory, coagulation, and fibrinolytic systems, has accelerated the development of novel treatments [88, 111]. Some of these drugs being researched and developed are peptides that hold great promise as therapeutic agents for treating sepsis [112,113,114]. As amino acids can be used in infinite arrangements in peptide synthesis, then peptides can be designed to have a wide range of unique physicochemical and biological properties. These unique properties include: 1) High specificity: Peptides may be designed to specifically target specific pharmacological targets, making their action highly selective with reduced off-target effects [115]; 2) Ability to target multiple pathways: Peptides can target multiple pathways in the sepsis cascade, which can help reduce the chances of antimicrobial resistance [19]; 3) Biodegradability: Inside the body, peptides are broken down into smaller biocompatible components, making them biodegradable with fewer side effects than traditional small molecule drugs [116]; 4) Ease of synthesis: Peptides can be synthesized using modern techniques in a laboratory setting, making it possible to produce cost-effectively large quantities of specific peptides for drug development [116]; 5) Permeability and bioavailability: some peptides can cross cell membranes, which increases their bioavailability and allows them to target intracellular targets in sepsis pathophysiology [117].

The properties mentioned above make peptide synthesis a promising approach for developing new diagnostic and management tools that can efficiently diagnose sepsis and effectively target both the bacteria causing sepsis and the pathophysiological pathways involved in the disease. For example, peptides have been designed to have strong and specific binding affinity to certain pathogens and inflammatory biomarkers, making them excellent capturing motifs for the diagnosis of sepsis [118]. Moreover, antimicrobial peptides have been shown to have potent bactericidal activity against Gram-negative and Gram-positive bacteria that are commonly associated with sepsis [119]. In addition to their antibacterial properties, peptides can target the pathophysiological pathways involved in sepsis, such as inflammation, oxidative stress, complement system, and coagulation [114, 120]. Furthermore, the excellent physicochemical and biological properties of peptides make them hold great potential as drug delivery systems construction materials for antisepsis drug delivery [121]. For example, peptides for drug delivery can be designed to respond to the characteristic microenvironment of sepsis, including acidity and high concentrations of reactive oxygen species (ROS) [121]. This allows for site-specific drug release, so good therapeutic outcomes with low side effects can be achieved with small doses of drugs that improve patient compliance and decrease the treatment cost. As a result, the application of peptides in sepsis diagnosis and management is an active area of research with promising outcomes that make them an attractive option in the battle against sepsis.

Application of peptides in nanotools for sepsis diagnosis and management

Sepsis continues to pose a significant global health challenge despite remarkable advancements in medical technology. Its high mortality rates and limited effective diagnosis and treatment approaches underscore the urgency to develop new, efficient, and novel techniques for accurate diagnosis and timely intervention [79, 122]. The application of nanotechnology-based tools presents a multitude of opportunities for advancing sepsis diagnosis and management [14]. With their distinctive properties, peptides have emerged as promising candidates for developing nanotools to combat critical illnesses like sepsis [112, 114]. Figure 2 provides a visual representation of the multiple roles peptides play as components within nanosystems for sepsis diagnosis and management. This section aims to explore and critically review the diverse range of research studies that have employed peptides as integral elements of nanotools for sepsis diagnosis and management, encompassing both pharmacological and pharmaceutical applications.

Fig. 2

A schematic illustration of various applications of peptides in nanotools for sepsis diagnosis and management (NPs: Nanoparticles; AIPs: Anti-inflammatory Peptides; AMPs: Antimicrobial Peptides) (Created with BioRender.com)

Peptides in nanotechnology for sepsis diagnosis

The timely diagnosis of sepsis is crucial to ensure effective treatment outcomes [78]. Although they can offer a promising avenue for early detection of sepsis, the use of peptides in developing nanotechnology tools for sepsis diagnosis is still in its infancy. Table 1 summarizes various studies done on the utilization of peptides in nanotools for sepsis diagnosis, highlighting the type of nanosystem, the peptide sequence, the role of peptide in the nanosystem, the targeted microorganisms or biomarkers, the mechanism of detection, the mode of investigation (in vitro and/or in vivo), and the key findings. As shown in the table, peptides have been mainly used for two different roles. The major role was using peptides as pathogen recognition moieties conjugated to the surface of magnetic or fluorescent nanoparticles to allow the capturing of bacteria and then separation or imaging. The other role has been the utilization of peptide as a thiol-rich moiety to enhance the binding of immuno-colloidal metallic nanoparticles to the surface of a mesoporous Surface-enhanced Raman scattering (SERS) template. It is clear that there is great potential for further research to uncover additional roles that peptides can play in nanotools for sepsis diagnosis. Moreover, most studies have focused on Gram-positive bacteria, indicating the need to address Gram-negative bacteria, which significantly influence the development of bacterial sepsis. The studies will be discussed according to the role of peptides in the nanosystem in the following subsections.

Table 1 Summary of peptides utilization in nano-diagnostics for bacterial sepsis Peptides as pathogen capturing motifs on nanoplatforms   

To date, various approaches for detecting, capturing, and separating bacteria from blood have been developed to improve the diagnosis and management of bloodstream infections [126, 127]. Various pathogen recognition molecules, such as aptamers, antibodies, oligonucleotides, and carbohydrates, have been used to modify nanoplatforms for pathogens detection and separation [19, 128, 129]. Since the bacterial surface displays unique molecular compositions, a well-designed peptide can have a specific and robust interaction with an epitope or a receptor on the bacterial walls. When engineered on the surface of nanoparticles, these peptides will yield an efficient nanotool for pathogen capturing with improved efficacy in sepsis diagnosis [130]. The subsequent paragraphs will discuss the findings of various studies that have investigated the utilization of peptides as capturing motifs exhibited on magnetic nanoparticles or fluorescent quantum dots to fabricate nanoplatforms for pathogen detection and then isolation or imaging.

Magnetic nanoparticles are promising nanoplatforms that can be effectively engineered with peptides as pathogen-capturing motifs for detecting and separating bacteria from human samples in simple and controllable processes [79,