Sepsis represents a severe and heterogeneous clinical syndrome that is described as life threatening organ dysfunction resulting from a dysregulated host response to infection (Singer et al., 2016). As a global health priority recognized by WHO, sepsis affects tens of millions of people worldwide and represents almost 20% of deaths on Earth each year (Reinhart et al., 2017; Rudd et al., 2020). Immunopathy is central to the pathogenesis of sepsis, which is characterized by a profound immune imbalance involving both hyperinflammation and immunoparalysis that disturb the homeostasis of the host and promote life-threatening organ injury (van der Poll et al., 2017; van der Poll et al., 2021). Specifically, sepsis occurs when an abundance of microbial cell-wall components, namely, pathogen-associated molecular patterns (PAMPs), along with cellular injury and the secretion of danger associated molecular patterns (DAMPs)—bind to pattern recognition receptors to initiate a network of inflammatory responses that promote tissue injury and organ dysfunction. Meanwhile, sepsis also induces systemic and sustained immunosuppression, as shown by tolerant reprogramming of innate immune cells, expansion of suppressive myeloid cells, and overwhelming apoptosis and exhaustion in T lymphocytes, resulting in increased susceptibility to secondary infection (Wang et al., 2022). These advances in our understanding of how sepsis occurs and develops have prompted translational investigations into the efficacy of immunomodulatory strategies. Unfortunately, few attempts have been considered successful despite decades of effort. Treating sepsis is still with remarkably limited therapeutic options (van der Poll et al., 2017). Therefore, innovative strategies are in increasing demand to achieve effective immunomodulation, which may help to improve the clinical outcome of sepsis.

Given the inherent challenges that impede the efficacy of conventional therapeutic agents such as poor bioavailability and lack of specific targeting, the emerging nanoparticle (NP)-based therapeutics have revolutionized the biomedical field, providing alternative approaches that may dramatically overcome the deficiencies of traditional therapies. Specifically, the controllable physicochemical features of NPs, including size, shape, and surface properties, lead to highly increased stability and bioavailability (Guo et al., 2021; Pant et al., 2021). Further, the surfaces of NPs can be diversely functionalized, which can greatly improve their capacity for targeted delivery to specific cells or tissues. These advantages have thus prompted research into develop promising immunomodulatory nanosystems that facilitate the adjunctive therapy of sepsis and other immunological disorders (Feng et al., 2019; Lasola et al., 2020). Non-etheless, naked NPs may be rapidly internalized by phagocytes (e.g., monocytes and macrophages) before performing their intended function. Their potential contact-toxic effect is another concern for their broad application. In this case, the development of biomimetic NPs may provide an alternative solution. Biomimetic NPs are artificially manufactured hybrids with both nano and natural materials (Meyer et al., 2015; Thorp et al., 2020). A typical biomimetic NP is made up of a definite core nanostructure that mimics the size and shape of cells or microbes, along with a camouflaging surface structure composed of biological membranes or membrane-anchored components (Meyer et al., 2015). Importantly, biomimetic NP are increasingly used for immunomodulatory purposes in treating sepsis, including inflammation targeting (Jin et al., 2018), anti-infection (Zhao et al., 2021), and immune cell activation (Lasola et al., 2020). In this regard, this minireview discusses the basic features of biomimetic NPs and their recent advances in developing potential remedies for sepsis treatment while highlighting the biomimicry properties underlying their immunomodulatory effect.

The successful management of sepsis relies heavily on early diagnosis and effective intervention. Nanotechnology has become increasingly recognized to meet these demands due to the inherent properties of nanomaterials that enable 1) imaging of infection, 2) capture and clearance of pathogens, PAMPs and DAMPs, 3) targeted delivery of therapeutic agents for antimicrobial, anti-inflammatory, anti-oxidant and immunomodulatory purposes (Pant et al., 2021; Papafilippou et al., 2021). First, many classes of NPs are used as core materials in sepsis management, including polymers, liposomes, metals and inorganic NPs. Metal NPs are preferentially utilized for the diagnosis of infection due to their unique optic features (Pant et al., 2021). Polymeric NPs and liposomes are more frequently employed to encapsulate therapeutic agents to increase bioavailability, tolerance and targeting (Papafilippou et al., 2021). For example, FDA has approved the use of liposomal formulations containing anti-fungal amphotericin B to treat fungal infection, an increasingly frequent cause of sepsis (Stone et al., 2016). Second, the sizes of these NPs are diversified based on the context of application in treating sepsis. Specifically, smaller particles (5–20 nm) are preferentially used for diagnosis while larger particles (100–200 nm) are mostly employed as targeted drug carriers or for clearing purposes. Third, functionalization with chemical or biological moieties is another feature that decide the use of NPs in sepsis. Indeed, functionalized NPs are advantaged to naked NPs by demonstrating decreased toxicity, increased retention and targeted delivery. These advantages are important for enhancing the efficacy and specificity of cargo antibiotics or anti-inflammatory agents. In particular, there is growing interest to develop biomembrane-camouflaged NPs for treating sepsis (Ismail et al., 2022). These particles not only preserve the required advantages of synthetic nanomaterials by also inherit the inherent beneficial features of natural biological surfaces, such as decreased immunogenicity and toxicity, increased blood retention, and controllable targeting (Meyer et al., 2015).

Nanoparticles become biomimetic when coated or camouflaged with biological membranes that form core-shell structures, leading to combinatory activity featuring both the versatility of nanomaterials and the functionality and biocompatibility of the biomembrane system (Jin et al., 2018; Sushnitha et al., 2020). Hence, coating with a biomimetic membrane may greatly improve the stability, retention, and combability of naked NPs. Meanwhile, the selective utilization of membrane-targeting dependent mechanisms preserves a variety of bioactivities such as recognition, binding, delivery, or cellular modulation while avoiding potentially unfavorable effects due to the absence of cellular contents (Thorp et al., 2020; Oroojalian et al., 2021). Generally, biomimetic NPs are manufactured based on the following elements: 1) a core nanostructure of synthetic polymers or liposomes that are stable, inert, or cell-mimetic (e.g., size and shape); 2) a coated biomembrane, membrane-like structure, or membrane components (e.g., proteins and polysaccharides); and iii) an assembly strategy for loading and coating separated biological membranes onto nanomaterials. The representative NPs coated with biological membranes or membrane components currently applied in sepsis therapy are summarized in Figure 1.

Sepsis is characterized by a dysregulated immunity that originates from infection, whose development involves the production of PAMPs, toxins, DAMPs, and inflammatory mediators that harm the host via a concurrent course comprising both excessive inflammation and immunosuppression (van der Poll et al., 2021). In this regard, immunomodulatory effects may be realized directly by biomimetic NPs to reverse these abnormities. Furthermore, other indirect mechanisms are also employed, such as the targeted delivery of immunomodulatory agents or augmenting their bioactivity. Table 1 and Figure 2 summarize the immunomodulatory effects of biomimetic NPs in sepsis treatment. In Table 1, the features of NPs and models regarding the purposes of immunomodulation has also been describes.

In general, RBC and macrophage membranes are preferable sources of coating membranes while PLGA NPs are commonly chosen as the core material. In addition, the particle sizes usually exceed 100 nm, making them retentional and readily available for any immunomodulatory purpose in sepsis treatment. In addition, the doses are decided by the cargo the NPs carry and by the definite roles of immunomodulation. For example, immunization requires far less amounts of NPs than anti-infectious or anti-inflammatory purpose. The use of laboratory sepsis models is another key aspect. Sepsis models can be simply classified as injection models and surgical models due to their methodology differences. In the injection models, pathogens or pathogen products [lipopolysaccharide (LPS), etc.] are locally or systemically administrated to induce sepsis. In the surgical model, the host barriers are disrupted by surgical operations, allowing a natural course of endogenous infection and sepsis (Wang et al., 2022). The cecal ligation and puncture (CLP) model is the most widely used surgical model in which sepsis is recapitulated by the surgery of cecal ligation and needle puncture that induce abdominal infection. The CLP model replicates a complete course of sepsis and is particularly suitable for evaluating the clinal relevance of immunomodulatory properties of biomimetic NPs (Wang et al., 2022). However, the inconsistency of outcomes may greatly hinder its wide use (Wang et al., 2022). In contrast, bacteria or LPS injection is relatively simpler and more stable. They can also be used to evaluate the specific purposes of targeted therapy. For example, the efficacy against methicillin-resistant Staphylococcus aureus (MRSA) sepsis can be examined by directly injection of MRSA in model animals. Therefore, these models are more preferentially used to preliminarily examine the immunomodulatory efficacy of biomimetic NPs in sepsis treatment.

The past decades have witnessed major breakthroughs in biomedical nanotechnologies and their potential application as tools for controllable immunomodulation in various diseases including sepsis (Fang and Zhang, 2016; Riley et al., 2019; Lasola et al., 2020). A variety of lipid based, polymer-based and inorganic NPs have been approved by FDA for clinical use, including the anti-fungal agent of amphotericin B liposome formulations that treats fungal infection and fungal sepsis (Mitchell et al., 2021). Non-etheless, the applications of NPs have been significantly impeded due to their inherent nature as foreign bodies (Parodi et al., 2020). However, the technique of membrane-coating has demonstrated remarkable enhancements in NP tolerance and stability. These biomimetic NPs have also demonstrated improved performance for immunomodulatory purposes, including anti-infection, inflammation control, reversing of immunosuppression, and targeted delivery with immunomodulatory agents, which strongly indicates their potential application in treating sepsis (Wang et al., 2020). Although most of these investigations are still in their early stages while no marked biomimetic NPs are currently available, biomimetic NPs have already addressed some of the limitations of both conventional therapeutic agents (e.g., poor bioavailability and lack of specific targeting) and naked NPs (e.g., short retention and immunogenicity). In this regard, biomimetic nanomedicine will undoubtedly aid the development of novel sepsis therapeutics.

Despite the encouraging results described above, there is still a long way to go before their actual application in treating sepsis. The first unresolved issue is the uniformity of the particles and the integrity of the coating membranes, thereby significantly affecting the efficacy and safety of the biomimetic NPs due to these inadequacy of quality (Li et al., 2020). Second, the proof of concept for the reproducibility and long-term stability of biomimetic NPs have not been verified, which also greatly affect their translational values into clinical use (Ismail et al., 2022). Third, most of the fabrication process of biomimetic membranes onto NPs was performed in the experimental settings whereas scaling-up techniques needed to be further developed to meet the requirement of large-scale clinical use. Fourth, the biosafety of the biomaterials employed for the design of such bioinspired nanocarriers should be confirmed. The above-mentioned promising findings were exclusively obtained in laboratory in which the sources of membrane or membrane components and the long-term stability and safety of the particles used for therapeutic purposes were not taken into consideration (Papafilippou et al., 2021). Actually, the side effect or off-target effect for the entire particles or the degraded core- and shell-structures as well have not been comprehensively examined. These unanswered questions must be answered before the clinical translation into sepsis therapeutics. On the other hand, challenge may also come from sepsis itself. Standard preclinical animal models are still lacking, which cannot precisely recapitulate the pathophysiology of human sepsis, including infection, inflammation, immunosuppression and organ dysfunction. In this regard, almost all the therapeutic agents which were effective in animal models of sepsis have not proved their efficacy in clinical trials. Consequently, more evidences are needed to prove the advantages of biomimetic NPs in animal models which can be replicated in human patients. Furthermore, sepsis has been unprecedently regarded as a heterogeneous disease, with dynamic changes in inflammation and immune status. Therefore, future efforts are needed to improve the NP coating strategy, to fully evaluate their pharmaceutical properties and to develop diversified biomimetic NPs that may meet the demands of precise therapy for sepsis, rather than simply targeting a specific aspect in the course of sepsis.