The rapid and accurate determination of infection is crucial for the diagnosis and early treatment of sepsis, thus facilitating the prognosis of patients. There are several traditional means of pathogenic diagnosis in sepsis, including culture-based techniques, polymerase chain reaction (PCR) and second-generation sequencing technology. The primary limitations of the above mentioned methods are as follows: (1) Results are not available for several days, which can delay the start of treatment; (2) Approximately 35% of cases that are initially suspected to be septic test negative in culture tests, potentially leading to misdiagnosis; (3) These methods frequently exhibit low sensitivity and specificity, which may result in the inaccurate identification of pathogens (Salomão et al., 2019). Therefore, there is an urgent need for technologies that can not only rapidly and accurately detect infections but also reliably identify pathogens and their functional traits.

Recently, nanomaterials have shown great promise in developing more sensitive and specific diagnostic tools for early bacterial infection detection. In particular, nanomaterials have been extensively studied for their detection capabilities. Functionalized with therapeutic antibiotics, antimicrobial peptides or active compounds, NPs selectively bind to components of the bacterial cell wall, such as lipopolysaccharides (LPS), or peptidoglycan. For instance, Zhu et al. demonstrated that Au NPs modified with ethanolamine and Escherichia coli O111:B4 LPS could be used to detect LPS through a color change mechanism. This is achieved by the binding of aptamers (G-probes) to ethanolamine, a component found in all LPS variants, causing the Au NPs to aggregate and shift color from red to blue. Furthermore, magnetic nanoparticles (MNPs) and carbon nanotubes (CNTs) have been explored for their potential in bacterial detection, offering new avenues for rapid and accurate diagnostic methods (Zhu et al., 2019).

Septic biomarkers, including procalcitonin (PCT) (Reinhart and Meisner, 2011), C-reactive protein (CRP) (Eschborn and Weitkamp, 2019), and IL-6 (Eichberger and Resch, 2022), have been identified for clinical diagnosis and management of sepsis. However, their sensitivity and specificity are limited, underscoring the urgent need for more precise diagnostic tools. With the advantages of high speed, high sensitivity and portability, nanobiosensors are suitable for bedside rapid and simultaneous detection of these biomarkers (Alba-Patiño et al., 2022).

Conjugating nanomaterials with antibodies or peptides that target sepsis biomarkers specifically can identify and quantify sepsis biomarkers by capturing significant alterations in the nanomaterials’ electrical conductivity or fluorescence intensity via the unique binding. Nanomaterials-based chemical biosensors have shown great potential in sepsis biomarker sensing due to their distinctive properties, such as carbon nanotubes (CNTs), Au NPs (Munge et al., 2009), and MNPs. In addition, electrochemical biosensors based on nanomaterials can achieve high-sensitivity and minimal-sample-amount detection of PCT in undiluted serum, which exhibit good correlation with the conventional ELISA method, but with less time consumption.

Nanotechnology has risen as innovative tools for diagnosing and monitoring sepsis. Based on the principle of nuclear magnetic resonance, magnetic resonance imaging (MRI) is designed to obtain detailed images of the internal structures of human body. For example, superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively researched for their use as MRI contrast agents in sepsis imaging, enhancing the visualization of affected areas. Furthermore, optical imaging, a non-invasive technique that employs light to illuminate organs and tissues, is another valuable approach. Near-infrared fluorescence (NIRF) imaging, capitalizes on the near-infrared light’s ability to penetrate biological tissues, providing superior imaging capabilities for detecting sepsis. In addition, since the cell metabolism in areas of inflammation and infection is hyperactive, positron emission tomography (PET) technology can be applied to detect sepsis-induced specific tissue injuries, the degree of inflammatory activity, assisting clinician to design the treatment strategies and evaluate patient outcomes. Radiolabeled NPs, functionalized with targeting ligands that selectively bind to sepsis biomarkers, enable targeted imaging of specific infected tissues, such as iron oxide or Au NPs. These radiolabeled NPs have been recognized as potential PET contrast agents in sepsis diagnosis. For instance, a nano-radiotracer combining neutrophil-specific biomolecule and hydrophobic peptide on the surface of ⁶⁸Ga core-doped nanoparticles has been established to evaluate the acute and chronic inflammation by labeling neutrophils (Pellico et al., 2017). These radiolabeled NPs show huge potential application for real-time and rapid monitoring the development of sepsis.

Nanomaterials can be engineered through surface modification to specifically target sepsis-induced certain cells or tissues, thereby enhancing the sensitivity and specificity of these non-invasive imaging technologies. Besides, radiolabeled nanomaterials-based PET technology detects accurately the biological processes and detailed lesions of suffered organs, providing more comprehensive diagnostic information for sepsis management. Unlike traditional invasive diagnostic methods, novel nanomaterial-based diagnostic strategies show great potential in reducing the risk of sepsis-associated complications. Additionally, by determining the exact location, microstructure, metabolic status and severity of the suffered organs in sepsis, the combination of different nanomaterial-based imaging technologies provide great potential for future patients, enabling accurate identification and continuous monitoring of sepsis.

The advantage of nanomaterials-based antibiotic therapy in treating sepsis depends on the development of nanotechnology, achieving improved physicochemical properties of drugs, targeted and controlled antibiotic delivery, and appropriate pharmacokinetic profile (Liu et al., 2019; Gupta et al., 2019). Au NPs with β-lactam antibiotic-metallopolymers system displayed enhanced antibacterial effect, in which Au NPs served as excellent carriers for antibiotics. On the one hand, cationic metallopolymers insert into bacterial membranes via their hydrophobic groups, and the antibiotic-metallopolymers bioconjugates protected against the hydrolysis by the bacterial β-lactamase enzyme, thus regaining the activity of conventional antibiotics. On the other hand, the inherent advantages of Au NPs further enhanced the concentration of antibiotics in pathogenic bacteria, including small size for high permeability, high surface area for high loading capacity, surface modification for high targeting, etc (Yang et al., 2019). Shaker et al. demonstrated that grafting carbapenem on Au NPs increased the antibacterial efficacy of carbapenem against clinical resistant Gram-negative bacteria in vitro, suggesting that Au NPs could be a superior delivery vehicle for antibiotic, especially in the MDR infections (Shaker and Shaaban, 2017).

The liposomal formulation of amphotericin B, an antifungal agent used to treat fungal infections and fungal sepsis (Mitchell et al., 2021; Anselmo and Mitragotri, 2019; Stone et al., 2016), encapsulates the active ingredient amphotericin B within the bilayer of small (∼80 nm median size) unilamellar liposomes. AmBisome, marketed as Amphotericin B liposomes by Gilead Sciences, is as efficacious as the traditional version but can be administered at significantly higher doses due to its greater tolerability. First commercially available in 1997, AmBisome received FDA approval and is now accessible in over 58 countries worldwide, recognized as a safe and potent therapy for severe systemic fungal infections.

Dendrimers are highly branched and symmetrical macromolecules with multiple branches emanating from a central core (Gillies and Fréchet, 2005). Dendrimers can encapsulate hydrophilic and hydrophobic drugs and can be functionalized with targeting moieties (Choi et al., 2013). Ji et al., prepared the optimized telodendrimer (TD) nanocarrier for encapsulating monomeric Amphotericin B (AmB) to fine-tune the aggregation status of AmB, thus enhancing the antifungal activity and reducing the cytotoxicity (Ji et al., 2023). With the hydrophilic exteriors and interiors, dendritic NPs maintain the property of unimolecular micelle to engineer precisely core structures for AmB encapsulation (Abbasi et al., 2014).

Characterized with controlled sizes and surface properties (Bernardos et al., 2019), silica NPs usually possesses high loading capacity for antibiotics, as well as protection against degradation of the agent. Additionally, Alavi et al. evaluated the antibacterial effect of the loading of nafcillin (NF) into a (PEG) ylated liposome (PEG-Lip-NF), which was a promising strategy against methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia and biofilm-associated infections (Alavi et al., 2022). Nafcillin encapsulated by PEG-coated liposome exhibited more potent anti-MSSA activity in the MIC and MBIC50 tests, decreased virulence, and increased survival rate induced by MSSA bacteremia, compared with NF-loaded liposome or NF alone. Surprisingly, PEG-Lip-NF decreased the NF-provoked nephrotoxicity in the MSSA infected animals (Alavi et al., 2022), suggesting that PEGylated liposome is a promising nano-carrier in MSSA infection.

To reduce the toxicity of colistin, a novel colistin formulation was designed, which was prepared with colistin antibiotic cross-linked micelles (ABC micelles) in aqueous solution by a novel one-pot method (Figure 3A). As we known, colistin characterized by its amine-rich structure and a solitary hydrophobic tail, possesses an exceptional capacity to bind to and destabilize the outer membrane of bacteria, destroying the integrity of membrane to release the components of infected bacteria, ultimately contributing to bacterial death. However, its amine-rich composition also leaded to nephrotoxicity and neurotoxicity, presenting a significant dose-limiting issue. In the study conducted by Yang et al., the terminal hydroxyl group of Pluronic F127 was activated with p-nitrophenyl chloroformate (NPC) to facilitate a reaction with the amine groups of colistin (Yang et al., 2021). Consequently, a portion of colistin was cross-linked with micelles, which not only reduced the amine-rich toxicity but also encapsulated the remaining of free colistin. Thus, compared with the existing conventional therapies, nanomaterial-based strategies exhibited same safety and higher efficacy. At temperatures around 4°C, these ABC micelles, unreacted Pluronic, and loosely bound surfactants dissociate into Unimers. Subsequently, the free colistin can be purified through low-temperature centrifugal filtration, yielding purified ABC micelles with a high concentration. This innovative approach has resulted in ABC micelles that not only substantially boost the encapsulation of antibiotics but also notably diminish systemic toxicity in mice. The mice were challenged with a multidrug-resistant strain of E. coli and subjected to various treatments, as illustrated in Figure 3B. The toxicity assessment, as presented in Figure 3C, revealed that the ABC micelles were well-tolerated, demonstrating a remarkable increase in the maximum tolerated dose (MTD) by at least 16-fold when compared to free colistin. Most notably, the group treated with colistin-ABC micelles experienced a significant enhancement in survival rates, comparing with the other treatment groups (Figure 3D). Furthermore, the biodistribution of ABC micelles was characterized by a preferential accumulation in the liver and spleen, with a significant reduction in kidney uptake, as shown in Figure 3E (Yang et al., 2021).

The deployment of these NPs in antibiotic delivery represents a promising frontier, offering distinctive attribution and functionalities. These have the potential to enhance drug efficacy, refine targeted therapies, reduce the toxicity of antibiotic, and retune the drug profiles of absorption, distribution, metabolism and excretion (ADME). Nonetheless, it is imperative to recognize that the ongoing research is dedicated to thoroughly assessing their safety profiles in the long-term implications of biomedical applications.

Antimicrobial peptides (AMPs) are an important part of the innate immunity of host, and are regarded as natural antibiotics synthesized by various organisms, including mammals, plants, protozoa, fungi, and bacteria. AMPs have amphipathic or cationic structural compositions and display a wide range of antimicrobial activity, targeting both Gram-positive and Gram-negative bacteria, fungi, viruses, and protozoa (Huan et al., 2020). Compared with traditional antibiotics, AMPs exhibit stronger immunomodulatory ability, contributing to the elevated innate immunity and acquired immunity by modulating various immune cells. Owing to the unique bacteria-lysing mechanism and anti-MDR property, AMPs has gained much attention in anti-infection field (Tan et al., 2022). However, the immature stability, uncertain safety profile, higher nephrotoxicity and neurotoxicity of AMPs hindered the research and potential application for sepsis therapy.

To solve these problems, a self-assembled NPs loaded with of human alpha-defensin 5 (HD5), a natural AMP secreted by intestinal Paneth cells, was designed and prepared (Figure 4A), with improved stability, bio-safety, and antibacterial potency (Lei et al., 2018). The nanobiotic-based formulations for drug-specific targeting exhibited significantly enhanced broad-spectrum bactericidal activity in vitro against various pathogens, including S. aureus, MRSA, Escherichia coli (E. coli), etc., compared to the free HD5 (Figure 4B). The analysis of organ injury scores, as presented in Figure 4C, fully supports these observations, highlighting the HD5-myr nanobiotic’s capacity to safeguard mice against sepsis. As illustrated by Figures 4D,E, HD5-myr nanobiotic treatment significantly reduces the mortality and organ damage in MSRA and E. coli-induced septic murine model, favoring the self-assembled HD5-myr nanobiotic in the application prospect for bacterial sepsis management.

In addition, Tan et al. synthesized antibacterial peptide (KR-12: KRIVKRIKKWLR)-grafted amphiphilic block copolymer and biotin grafted block copolymer, which were co-assembled in an aqueous solution to produce the AMPNP (Tan et al., 2022). In this work, the in vitro predominant antibacterial activity of the prepared NPs was confirmed, including E. coli, S. aureus, and MRSA. Moreover, in a septic mice model, both nanosystems showed a more pronounced reduction in serum cytokines (IL-1β, TNF-α, and IL-6) and inflammatory infiltration in target tissues compared to the uncoated AMPNPs. Saúde et al. have encapsulated the antimicrobial peptide Clavanin A in a polymeric matrix for bacterial sepsis control, aiming to improve its stability and therapeutic efficacy (Saúde et al., 2014). A polymicrobial sepsis model of mice was adopted to evaluate the in vivo efficacy of the nanoantibiotic Clavanin A, which showed a 100% survival rate under a sub-lethal dose of bacteria and a 40% survival rate with a lethal inoculum, along with improved antimicrobial activity and druggability.

The micellar form of CG3R6-TAT peptide, presented as nanodots, has demonstrated efficacy in curing sepsis-induced meningitis in the central nervous system, as reported by Martin et al. (2015). By modifying the antimicrobial peptide HHC36 (KRWWKWWRR) with the aggregation-induced emission (AIE) molecule 2-(2-hydroxyphenyl)benzothiazole (HBT), an AIE probe named AMP-2HBT was prepared. This probe not only retains the antimicrobial activity of the HHC36 peptide but also allows for real-time observation of the binding process between the antimicrobial peptide and bacteria, thus revealing the mechanism by which the antimicrobial peptide HHC36 kills bacteria by disrupting the structure of bacterial membranes (Chen et al., 2018). Additionally, polyprodrug antimicrobials, such as triclosan and methacrylate, have been synthesized and have shown significant therapeutic efficacy against methicillin-resistant S. aureus, as documented by Schuerholz et al. (2012).

There is no doubt that nanomedicines loaded with antimicrobial peptides have great potential in the sepsis management, but there are still many problems to be solved from basic to clinical research. Indeed, many clinical trials nanomedicines of antimicrobial peptides in the treatment of sepsis are still in their infancy, and a large number of relevant clinical data need to be collected for the specific therapeutic dosage, therapeutic time window and the administration routes. What’s more, much more attention should be paid to the antimicrobial peptides resistance in the future research.

Cell membrane-coated nanoparticles (MNPs) are the novel biomimetic NPs that are created by the surface of synthetic NPs with natural cell membranes. MNPs retain both the physicochemical properties of synthetic nanomaterials and the inherent functions and features of the origin cells, such as “self-labeling” and the interaction with immune system. Therefore, MNPs possess better biocompatibility and weaker immunogenicity, enabling them to evade the immune clearance. Unlike other nanoparticles, the targeted delivery of MNPs is achieved by the recognition mechanism of engineered membrane proteins on MNPs to ligands, which allows for more efficient delivery of encapsulated drug (Sushnitha et al., 2020; Oroojalian et al., 2021). Herein, we summarized the progress of three main categories of MNPs achieved in sepsis treatment.

Macrophages are phagocytes in the innate immunity dedicated to the recognition of foreign substances, including NPs, with which an immune response subsequently occurs. Various design strategies, such as surface functionalization, have been implemented to manipulate the recognition and engulfment of NPs by monocytes/macrophages, regulating their function in sepsis, and compensating for the shortcomings of anti-infective conventional strategies (van der Poll et al., 2017; Locati et al., 2020). Considering the critical role of prolonged oxidative stress in sepsis-associated injuries, a novel H₂O₂ scavenger platform was developed by assembling bovine serum albumin/manganese oxide (BSA/MnO2) nanoparticle onto mannosylated disulfide cross-linked polyethylenimine (ssPEI) (mSP) (Rajendrakumar et al., 2018). This synthesized nanoassemblies improved the stability of MnO2, specifically inhibited the production of H₂O₂-mediated free radicals, rather than other superoxide free radicles. The highly stable mSPAM nanoassembly inhibited HIF1α expression by clearing H₂O₂ in LPS-induced macrophages, decreased serum TNF-α and IL-6 levels, and reduced infiltration of neutrophils and other white blood cells in endotoxemia models, thereby avoiding subsequent organ damage induced by inflammatory macrophages. More recently, a nanomedicine for conditioning macrophages was designed and prepared by coating the albumin-methyl palmitate with spherical nanoparticles (namely, spherical methyl palmitate nanoparticles, MPN), which can effectively transport natural fatty acids and temporarily inhibit the uptake of nanomaterials by resident macrophages (Palomba et al., 2021), providing a new idea for macrophages-targeting sepsis management.

The intricate pathophysiology of sepsis alters the phenotype and function of macrophages, leading to a state of macrophage exhaustion. Currently, there is a dearth of drugs that effectively targeting macrophage function and a lack of robust methods for detecting macrophage activity. Encapsulated and sequestered the active pharmaceutical ingredients, nanomaterials emerge as promising candidate materials for macrophage targeting in sepsis, which enhance targeted delivery to macrophages over time and improve the biodistribution and bioavailability of drugs.

Natural products have long been used to prevent and treat various diseases, including inflammatory and immune-related disease (Gu et al., 2022). Due to their excellent anti-inflammatory, antibacterial and immunoregulatory potency in sepsis as well as the low cost, they have garnered considerable concern (Song et al., 2023). However, the low solubility, hydrophobicity and low bioavailability have limited their broader application of them in clinical (Huang et al., 2022). In recent years, researchers have paid more and more attentions to using nanomaterials load natural products, reducing the side effect of them and control the drug release for nanosystems. Herein, we summarize natural products that have been loaded into nanosystems for sepsis treatment in Table 1, such as curcumin (Cur), tea polyphenols, resveratrol and so on. As shown in Table 1, Wang et al. successfully prepared and evaluated Cur-loaded solid lipid nanoparticles (Cur-SLNs) for sepsis (Wang et al., 2015). In vitro experiments indicated that Cur-SLNs can effectively reduce levels of IL-1β, TLR4, TLR2, and TNF-α. Meanwhile, the results showed suppression of NF-κB activation and IκBα degradation levels. Similar results were observed in vivo experiments. Altogether, they proposed that Cur-SLNs could serve as a promising therapeutic drug delivery system for LPS-induced sepsis through the TLR2/4-NF-κB signaling pathway.

However, the majority of nanomedicines loaded with active natural compounds are still in the preclinical stage, and the release mechanism and its clinical therapeutic effect need to be further clarified.

Photothermal antimicrobial therapy represents an innovative treatment approach that utilizes light-induced heat to eradicate or inhibit the growth of kinds of pathogenic pathogens. These alternative options comprise photo-sensitive NPs and specialized dyes, etc., which are adept at absorbing specific light wavelengths and transforming that energy into thermal heat. In the realm of nanotechnology, nanozymes are nanomaterials that possess the intrinsic enzyme-like activities (Huang et al., 2019). As synthetic catalysts, nanozymes stand out as a potential substitute for natural enzymes across a variety of applications, notably in their capacity to eliminate bacterial infections (Zhang et al., 2021).