# Nanoparticle-based approaches for sepsis treatment: Current trends and perspectives

Younes Louaguenouni, Arnaud Mansart, Djillali Annane, Elias Fattal, François Fay

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Younes Louaguenouni, Arnaud Mansart, Djillali Annane, Elias Fattal, François Fay. Nanoparticle-based approaches for sepsis treatment: Current trends and perspectives. Journal of Controlled Release, 2025, 386, pp.114139. 10.1016/j.jconrel.2025.114139. hal-05324488

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# Nanoparticle-based approaches for sepsis treatment: Current trends and perspectives

Younes Louaguenouni<sup>a</sup>, Arnaud Mansart<sup>b,d</sup>, Djillali Annane<sup>b,c,d</sup>, Elias Fattal<sup>a,d,*</sup>,
François Fay<sup>a,d,e,*</sup>

## ARTICLE INFO

### Keywords:

Sepsis

Nanomedicine

Inflammation

Immunomodulation

## ABSTRACT

Sepsis is a devastating syndrome resulting from organ dysfunction caused by a dysregulated host response to infection. The management of patients is currently primarily based on controlling the infection and restoring cardiovascular/respiratory homeostasis. Unfortunately, except for systemic corticosteroid therapy, no approved immunomodulatory treatment for sepsis exists. However, the ability of nanoparticles to cross biological barriers and deliver therapeutic agents in a targeted manner makes them particularly attractive to hinder a number of mechanisms within sepsis pathology.

While historically, nanoparticles have been predominantly developed for antimicrobial strategies, in the last few years, several remarkable studies have demonstrated the possible application of nanomaterials to hamper either early acute inflammation or sepsis-induced immunosuppression. Thus, this review summarizes current knowledge on nanoparticle-based therapies to address the complex multicellular pathways activated during sepsis. The strategies presented here encompass a wide range of interventions, from antibacterial and cleansing techniques to cell-specific modulation of both hyper and hypoinflammation. Finally, nucleic acid-based therapies are discussed, as new RNA-loaded nanoparticles to treat sepsis have very recently emerged.

## 1. Introduction

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to a bacterial, fungal, or viral infection resulting in life-threatening organ dysfunctions. Recent studies have revealed that the most common starting events are respiratory tract infections, followed by urinary, abdominal, and cutaneous infections [1,2]. Apart from anti-infective treatments, restoring and maintaining respiratory and cardiovascular homeostasis, there is no specific treatment for sepsis. Subsequently, sepsis mortality remains unacceptably high, and one out of two survivors is left with long-term sequels. The World Health Organization has recently estimated that every year, more than 49 million people, including 3 million newborns, are affected by sepsis, leading to 10 million deaths [3,4].

Over the past few decades, the use of nanotechnology has resulted in

significant breakthroughs in various biomedical fields. Nanoparticle-based strategies have been highly investigated for various clinical applications, such as biosensing [5], drug delivery [6], imaging [7], and anti-microbial treatments [8]. Indeed, nanoparticle-based approaches enable the delivery of new drug moieties, improve the drug routing to the designated target site, and reduce off-target accumulation [9]. These breakthroughs have led to the development of new pharmaceutical products such as Gastromark™ (oral delivery of superparamagnetic iron oxides [10]), DepoCyt™ (local delivery of Cytarabine [11]), Estrasorb™ (estradiol topical emulsion [12]), Doxil™ (systemic delivery of Doxorubicin [13]), AmBisome™ (liposomal formulation of amphotericin B [14]), and Onpatro™ (SiRNA delivery to the liver [15]).

In the context of sepsis, nanoparticle-based approaches are fairly novel but have already demonstrated therapeutic efficacy in preclinical models, with several of them having progressed to clinical trials. Herein,

<footnote><sup>a</sup> Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 91400 Orsay, France</footnote>

<footnote><sup>b</sup> Université Paris-Saclay, UVSQ, INSERM, U1173 2I, 78180 Montigny-le-Bretonneux, France</footnote>

<footnote><sup>c</sup> General Intensive Care Unit, Raymond Poincaré Hospital (AP-HP), University of Versailles Saint-Quentin en Yvelines, University Paris Saclay, 92380 Garches, France</footnote>

<footnote><sup>d</sup> IHU-SEPSIS, Comprehensive Sepsis Center, Raymond Poincaré Hospital (AP-HP), University of Versailles Saint-Quentin en Yvelines, University Paris Saclay, 92380 Garches, France</footnote>

<footnote><sup>e</sup> Institut Universitaire de France (IUF), France</footnote>

<footnote>* Corresponding authors.</footnote>

<footnote>E-mail addresses: elias.fattal@universite-paris-saclay.fr (E. Fattal), francois.fay@universite-paris-saclay.fr (F. Fay).</footnote>
we will explore in a chronopathophysiological way the different
nanoparticle-based approaches developed for managing sepsis, starting
with the antimicrobial strategies, followed by blood cleansing and cell-
specific immunomodulation, including the application of nanomaterials
to hamper either early acute inflammation or sepsis-induced immuno-
suppression. Finally, reflecting on the recent advancements in nano-
particles for nucleic acid delivery, we will explore the emerging use of
RNA-based nanotherapies and their potential applications in treating
sepsis.

1.1. Sepsis: Pathogenesis and current treatment

Infections are triggered by pathogens invading normally sterile tissues or compartments. The first line of defense relies on the innate immune system, particularly resident macrophages, monocytes, neutrophils, and dendritic cells. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) activate immune cells, which release in a timely fashion a broad variety of pro-inflammatory molecules such as cytokines and chemokines. Circulating monocytes quickly respond to this efflux of cytokines and migrate to the sites of infection [16]. There, they also become activated and start secreting pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-8 (IL-8), as well as reactive oxygen species (ROS). Compared to a localized infection, during sepsis, the immune response becomes dysregulated. A massive release of pro-inflammatory cytokines – commonly referred to as a “cytokine storm” is triggered through the Toll-Like Receptors (TLRs)/CD14 NF-κB pathway, which characterizes the apex of the initial phase of sepsis. The release of oxidizing agents, phospholipases, and proteases within this proinflammatory microenvironment can activate endothelial cells and damage the endothelial sidewall, thereby increasing vascular permeability [17] and the leakage of blood fluids into the interstitial environment, inducing hypovolemia. Initially, the hypovolemia can be compensated by an increase in cardiac output, but if the inflammatory processes persist or worsen, the compensatory capacities of the heart become overwhelmed, and the hypotension becomes more pronounced [18]. Sepsis may also cause a decrease in cardiomyocyte contractility, leading to myocardial dysfunction, exacerbating the hypotension even more. If not treated, this systemic inflammatory response and its vascular consequences may ultimately result in multiple organ failure

and possibly death [19] (Fig. 1). Recent works have revealed that for
certain patients, an excessive pro-inflammatory response can also lead
to the induction of an undesirable immune suppressive back-loop shift,
including anti-inflammatory cytokines production, T cell anergy, and
immune cell apoptosis [20]. This immunosuppressive state, also called
immune exhaustion, plays a significant role in increasing susceptibility
to subsequent infections and sepsis late mortality [21,22]. Thus, one of
the main hurdles encountered in the development of immunomodula-
tory treatments to treat sepsis is the coexistence of the lethal hyper-
inflammation reaction with this secondary immunosuppressive phase.

Unfortunately, aside from antibacterial regimens and glucocorticoid administration (Table 1), there are no drugs specifically marketed to treat sepsis [23]. Over the last decade, numerous progresses, including the recent use of artificial intelligence [24], have been made in understanding sepsis pathogenesis mechanisms and have led to the identification of an array of molecular targets throughout the different stages of sepsis [25–29]. Regrettably, the ability to translate these advancements into new clinical treatments has not yet been fully successful.

Various agents have been investigated, including anti-PAMPs and anti-cytokines neutralization molecules, antioxidants, immune receptor (TLR4, CD28) inhibitors, and broad anti-inflammatory drugs (glucocorticoids, statins) [30]. Additionally, recent studies have been focused on restoring patients’ immune system during sepsis-acquired immunosuppression using immunostimulatory agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-17 (IL-17), interferon γ (IFNγ), as well as inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1). While all these promising strategies have led to the conduct of more than 30 clinical trials, the majority of those studies have not demonstrated significant survival benefits in patients [31,32], except for AmBisome™, which is currently used in cases of fungal infection. Consequently, since the withdrawal in 2011 of Eli Lilly’s Xigris™ (Drotrecogin alpha), a recombinant form of activated protein C, which failed to confirm initial beneficial effects due to a significantly increased risk of severe bleeding [33], no molecular immune modulator therapeutics have been approved by regulatory agencies [34]. Several of the various pre/clinical failures can be linked to a lack of tissue or cell specificity, leading to poor clinical efficacy or detrimental off-target side effects.

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Comprehensive overview of molecular targets at different stages of sepsis pathogenesis and therapeutic molecules that have been tested.</figcaption></figure>
<table><caption>**Table 1**
Summary of main interventions during sepsis clinical management.</caption><thead><tr><th>Clinical intervention</th></tr></thead><tbody><tr><td>Early detection and immediate intravenous broad-spectrum antibiotic regimens, which should be adapted once microbiological culture results become available.</td></tr><tr><td>Hypotension and oxidative capacity monitoring, hemodynamic support with colloids/crystalloids perfusion, and administration of vasoactive drugs such as epinephrine or vasopressin if needed.</td></tr><tr><td>Early mechanical ventilation and oxygen administration via a face mask or endotracheal intubation if needed.</td></tr><tr><td>Hemodynamic support, glucocorticoids, and continuous renal replacement therapy if needed.</td></tr><tr><td>Blood glucose control through control of nutrition and potential insulin infusion therapy if needed.</td></tr></tbody></table>

## 2. Application of nanotechnology to treat sepsis

The multifaceted nature of sepsis, characterized by complex and overlapping pathophysiological events, is a significant challenge for the development of therapeutic approaches. One promising strategy to circumvent those hurdles has been the recent development of cell/tissue-specific nanoparticulate platforms. Nanoparticles can provide a tailored and versatile solution, offering the ability to address specific pathophysiological processes, including infection control, blood cleansing, and immunomodulation, with some of them being currently clinically tested (Table 2). Regarding immunomodulation, several groups have taken advantage of the recent progress demonstrated by the ability of nanoparticles to target immune cells in various diseases such as atherosclerosis, rheumatoid arthritis, and cancer to develop new nanoparticle-based immunomodulatory approaches toward sepsis [35–37]. Most of these strategies focus on resolving the hyper-inflammatory mechanisms involved in sepsis by delivering immunomodulatory molecules to target inflamed tissues or immune cells [38]. Additionally, a small but growing fraction of the recently published works aims to reduce sepsis’s immunosuppressive phase. In the next paragraphs, we will present recent developments and provide further insights on how nanoparticle-based platforms may be used to further improve clinical outcomes during sepsis.

### 2.1. Antimicrobial strategies

It is well recognized that the presence of pathogens or of their toxins or – in a normally sterile tissue – or compartment - is the primary initiating factor of the inflammatory cascade observed during sepsis as various studies have shown that the bacterial load is tightly linked to the disease severity and the mortality rate [39]. Thus, different nanoparticle-based strategies focusing on the direct clearance of the pathogen or its proinflammatory compounds have been developed to improve patients’ clinical outcomes. Indeed, nanoparticle-based strategies offer a versatile toolkit for improving antimicrobial efficacy in different ways. First, they can significantly improve the effectiveness and extend the half-life of antibiotics, reducing the administration frequency. Second, they can enhance the active targeting of bacteria within infected tissues. Finally, numerous nanomaterials exhibit potent

inherent antimicrobial properties, providing powerful means to combat antibiotic resistance. These multifaceted applications highlight the broad potential of nanotechnology in reshaping antibacterial approaches. This section will explore nanoparticle-based strategies applied across antibiotics, antimicrobial peptides, and antimicrobial nanomaterials. Moreover, it will specifically focus on strains frequently associated with sepsis, emphasizing how nanotechnology can robustly enhance antibiotics’ efficacy in this critical medical condition.

### 2.1.1. Nanoparticles to enhance tissue and intracellular distribution of antimicrobials

During sepsis, administering the appropriate antimicrobial at the adequate dose and timing is a critical prognostic factor. Nanotechnology has been considered an attractive new approach to enhance antibiotic delivery, as several types of nanoparticles, such as liposomes, polymeric nanoparticles, and solid lipid nanoparticles (SLNs), have been shown to increase the therapeutic efficacy and/or reduce the off-target toxicity of an array of antibiotics.

Mycobacterium strains have repeatedly been associated with sepsis [40–42]. Amikacin, an aminoglycoside antibiotic, is broadly used to treat bloodstream infections. Specifically, it is prominent in treating actinobacterial infections, such as non-tuberculous mycobacterial disease [43]. As amikacin requires frequent administrations and continuous therapeutic monitoring due to its kidney toxicity [44], a liposomal formulation of the drug has been developed by Nektar Therapeutics in order to improve its efficacy [45]. Preclinical studies showed that upon intravenous injection in a rat model, amikacin-liposomes disseminated to multiple tissues where they progressively released the drug, resulting in an eightfold increase in the drug’s half-life [46,47]. Local antibiotic administration is a proven method for increasing medication potency and reducing systemic toxicity. In 2018, the U.S. Food and Drug Administration approved a nebulized form of amikacin-liposomes developed to reach sufficient lung concentrations while restricting systemic exposure. Individuals who received amikacin-liposomes demonstrated a four-fold increase in intracellular amikacin levels compared to those treated with an equivalent amount of free amikacin [48]. Interestingly, a new clinical study has recently been set up to treat Mycobacterium Xenopi lung infection with an expected completion date in 2027 (NCT04378920).

<table><caption>**Table 2**
Clinical evaluations of nanoparticle-based strategies.</caption><thead><tr><th>Registered number</th><th>Clinical phase</th><th>Condition</th><th>Nanoparticles</th><th>Mechanism of action</th><th>Outcomes</th><th>References</th></tr></thead><tbody><tr><td>NCT00697944</td><td>Phase 4</td><td>ICU-acquired sepsis and multiple Candida infection</td><td>Amphotericine B in liposome (Ambisome)</td><td>Antimicrobial effect of patients with ICU-acquired sepsis and multiple Candida infection</td><td>AmBisome™ showed a manageable safety profile in patients</td><td>[67]</td></tr><tr><td>NCT06585020</td><td>Phase 2</td><td>Patients with Mycobacterium Xenopi Pulmonary Infection</td><td>Amikacin Liposome Inhalation Suspension</td><td>Delivery by inhalation should reduce renal and auditory toxicity of amikacin.</td><td>not completed (Estimated 2027)</td><td>NA</td></tr><tr><td>NCT02583373</td><td>Phase 1</td><td>Severe community-acquired Streptococcus pneumoniae</td><td>Mixture of liposomes</td><td>Binding of bacterial endotoxins</td><td>safe profile in patients<br>Phase 2 not completed (Estimated 2026)</td><td>[112]</td></tr><tr><td>NCT05776004<br>NCT04257136</td><td>Phase 2<br>Phase 2</td><td>Septic Shock</td><td>Phospholipid nanoparticles</td><td>Capture of Nitric Oxide in the blood and redistribution</td><td>Safe profile and activity in the treatment of hypotension and multiple organ failure in patients</td><td>[122]</td></tr><tr><td>NCT06072430</td><td>Phase 3</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>
Several studies have also been published demonstrating the potential of antibiotic-loaded SLNs to promote bacterial death inside macrophages [49–52]. An interesting approach to achieving tissue-specific drug delivery involves the development of pH-responsive SLNs. These nanoparticles can modulate their release rates based on the pH of their surroundings. When the SLNs reach the infection site, characterized by a lower pH, the change of pH initiates the antibiotic release within the targeted tissue [53,54]. Using this approach, Ma et al. decorated the surface of isoniazid-loaded-pH-sensitive SLNs with mannose to stimulate macrophage adhesion in a tuberculosis rat model infected with *Mycobacterium smegmatis*. The combination of the two targeting strategies led to a significant increase in intracellular delivery and higher efficiency compared to the free isoniazid solution. Specifically, the SLN-treated group exhibited a 83 % reduction in colony-forming units compared to a 60 % decrease for animals treated with free isoniazid [55].

Another interesting strategy is the use of polymyxin B-loaded liposomes [56], which have been shown to mitigate the adverse effects of the drug while concurrently enhancing its antibacterial efficacy against resistant strains of *Pseudomonas aeruginosa*, a pathogen known to be implicated in hospital-acquired sepsis [57]. The minimum inhibitory concentrations of polymyxin B-loaded liposomes were observed to be consistently lower in comparison to the free polymyxin B. Moreover, using microscopic studies, the authors demonstrated that penetration of polymyxin B into a resistant strain of *Pseudomonas aeruginosa* was improved when administered in a liposomal formulation. A similar approach was taken by Bakker-Woudenberg et al. to develop a liposomal strategy against *Klebsiella pneumoniae*, commonly associated with sepsis within intensive care units [58]. The authors demonstrated in rat models that Polyethyleneglycol (PEG)-coated liposomes exhibited extended circulation times in the bloodstream and notable accumulation within infected lung tissues. Administration of liposomes loaded with gentamicin or ceftazidime increased survival rates among the rats and reduced bacterial presence in the lungs compared to antibiotics alone. Furthermore, administration of a single dose of liposome-encapsulated ceftazidime was as effective as a two-day continuous infusion of non-encapsulated ceftazidime [59].

*Staphylococcus aureus* is also an opportunistic pathogen often found in the human anterior nares and a leading cause of sepsis and endocarditis [60]. Onyeji et al. conducted a study using liposomes loaded with teicoplanin and vancomycin to deliver antibiotics to infected human macrophages. Interestingly, their study showed that, while the encapsulation of the drugs inhibited their bactericidal effects against extracellular *Staphylococcus aureus* bacteria, it led to a significant increase in antibiotic uptake by the infected macrophages, resulting in enhanced clearance of intracellular bacteria [61]. Several other liposome-based antimicrobial drug delivery systems have also been developed, such as benzyl penicillin-loaded liposomes, which were shown to prevent the growth of a penicillin-sensitive strain of *Staphylococcus aureus* at a lower drug concentration and for a shorter period than free benzyl penicillin [62].

Polymeric nanoparticles have also been investigated to deliver a range of antimicrobial agents to treat various infectious diseases with enhanced therapeutic efficacy. For example, Ciro et al. explored the activity of ampicillin-loaded chitosan-polyanion nanoparticles against *Staphylococcus aureus* strains [63]. Interestingly, the minimal inhibitory concentration of encapsulated ampicillin was measured at 0.13 µg/mL compared to 0.26 µg/mL for free ampicillin. Walvekar et al. also observed this improved efficacy when using hyaluronic acid decorated polymeric nanoparticles to deliver vancomycin against *Staphylococcus aureus*, as in vitro studies showed that encapsulation led to a 1.8-fold higher bacterial mortality compared to free drug [64]. Although direct applications of antibiotic-loaded nanoparticles for sepsis treatment may be limited in the literature, the encouraging results presented above are promising ways for further research and development of sepsis therapeutics.

Since sepsis and secondary hospital-acquired infections can also be

caused by yeasts, particularly *Candida* species, nanoparticles have been investigated as delivery systems for antifungal agents. One of the most common antifungal agents, amphotericin B, is insoluble in saline at physiological pH and has been associated with multiple organ damage, including kidney damage. Several lipid-based formulations have therefore been developed to improve amphotericin B's intravenous bioavailability and reduce its side effects [65]. Those formulations are based on combining amphotericin B with either cholesteryl sulfate to form a colloidal dispersion (Amphocil™/Amphotec™, discontinued), with mixture of ditetradecanoyl-sn-glycero-phosphocholine and Dimyristoyl-sn-glycero-phosphoglycerol to produce a lipid complex (Abelct™), or with phosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol to obtain liposomes (AmBisome™). A retrospective meta-analysis focused on the use of amphotericin B for the treatment of systemic fungal infections revealed that both lipid complex and liposomal formulations of the drug led to a 28 % mortality risk reduction and 58 % renal toxicity reduction compared to deoxycholic acid amphotericin B [66]. While AmBisome™ is not currently used for general sepsis, it is a key treatment for invasive fungal infections, particularly in high-risk patients. The AmBiDex study (NCT00697944, Table 2) focused on the safety of high-dose administration in critically ill patients with ICU-acquired sepsis and *Candida* colonization. The study revealed that a 2-weekly administration of high-dose AmBisome™ has a manageable safety profile in those patients, as only a few patients experienced severe renal toxicity, and no significant increase in serum creatinine was reported, enabling the possibility of using the liposomal form of amphotericin B to treat sepsis patient against acquired secondary fungal infections [67].

### 2.1.2. Nanoparticle-based approaches to fight antimicrobial resistance

Antimicrobial resistance is a growing issue that makes treating sepsis increasingly difficult. As more germs develop resistance to the available antibiotics, numerous studies have looked at how resistance affects individuals with sepsis. In a prospective study conducted by Chow et al., the authors highlighted that the mortality was two times higher among patients with *Enterobacter* multi-resistant strains compared to patients with a more sensitive *Enterobacter* sp [68]. Later, Kim et al. investigated the impact of extended-spectrum β-lactamase (ESBL) production in strains of *Escherichia coli* and *Klebsiella pneumoniae* on the consequences of antibiotic treatment. Among patients with septic shock, mortality was 83 % in those with ESBL-positive strains compared with 11 % in those with strains without ESBLs [69]. A study examining mortality, antibiotic treatments, and antibiotic resistance among more than 3000 newborns with suspected neonatal sepsis at hospitals in 11 countries revealed that half of the deaths were related to hospital-acquired infections [70]. As these studies highlight the profound impact of antimicrobial resistance on sepsis outcomes, the development of nanoparticle-based approaches using antimicrobial peptides or innovative nanomaterials could become valuable tools to combat resistant bacterial strains.

### 2.1.3. Nanoparticle-based delivery of antimicrobial peptides against resistant bacterial strains

Antimicrobial peptides (AMPs) are amino acid sequences with an antimicrobial activity. Because of their highly rapid bacterial killing property, AMPs have emerged as a possible alternative therapy against multidrug-resistant bacterial infections [71]. Research on endogenous AMPs has revealed that the primary mechanism of action of most AMPs is linked to the permeabilization/disruption of the microbial cytoplasmic membrane [72]. Additionally, some AMPs have been shown to neutralize pathogenic substances such as lipopolysaccharides (LPS). Unfortunately, as with any peptide drug, upon *in vivo* administration AMPs can quickly suffer proteolytic degradation and a poor pharmacokinetic profile [73]. Thus, several groups have developed nanoparticle-based approaches to improve the stability and effectiveness of AMPs and decrease their toxicity [74–76]. Fan et al. developed a liposomal formulation combining levofloxacin with the short
antibacterial peptide S-thanatin. Compared to the levofloxacin lipo-
somal formulation, the combination of levofloxacin and S-thanatin
exhibited a synergistic effect with a significantly higher bacterial
clearance in a *Klebsiella pneumonia*-induced sepsis mouse model [77].
Interestingly, Ziu et al. managed to co-assemble two active lipopeptides
(i.e., a thiol disulfide oxidoreductase inhibitor and a membrane-
disrupting lipopeptide) to form a micellar structure encapsulating the
antibiotic cefoperazone. Imaging data revealed that the micelles can be
taken up by *Escherichia coli*, leading to the release of the 3 drugs and an
effective antimicrobial effect, demonstrated both *in vitro* and *in vivo*
[78].

Another interesting strategy is based on the development of nano-
particles decorated with peptides composed of valine and lysine resi-
dues, exhibiting a high antibacterial activity against an extensive range
of Gram-negative bacteria. The antibacterial action of these AMP-
decorated nanoparticles is believed to be achieved by the valine and
lysine residues that can induce membrane instability and activation of
'apoptosis-like' death pathways. Those nanoparticles were tested in a
peritonitis-mimicking model using a multidrug-resistant *Acinetobacter
baumannii* strain, known for its role in hospital-acquired infections such
as catheter-related sepsis [79], and for high mortality rates. Results
showed that the nanoparticles had a comparable efficacy to imipenem-
only treatment, leading to the reduction of bacterial counts by over five
logs in the peritoneal cavity [80].

1.1.1. Nanoparticles as inherent antimicrobial agents

In addition of being effective antimicrobial drug carriers, few
nanoparticles have been shown to possess inherent antibacterial prop-
erties. Several studies have indeed demonstrated the antibacterial effect
of metallic nanoparticles made of Silver (Ag) [81], Zinc oxide (ZnO)
[82], Copper oxide (CuO) [83], and Iron oxide (Fe₃O₄) [84] against both
gram-positive and gram-negative bacteria, as well as efficacy toward
biofilms. Those metallic nanoparticles have been shown to bind to
bacteria mediated by electrostatic attraction [85] and van der Waals
forces [86], leading to cell membrane disruption, osmoregulation
imbalance, enzyme inhibition, protein deactivation, or alteration of
gene expression (Fig. 2). Interestingly, as most of the mechanisms of
action do not target a precise molecular pathway, they are thought to be
less likely to generate bacterial resistance.

Having been shown to possess a high antimicrobial activity against
drug-resistant bacteria, silver nanoparticles (AgNP) are among the most
studied antibacterial nanomaterials and have previously been used in
various consumer products, including antimicrobial dressings for wound
therapy [87]. AgNPs have been shown to accumulate within the bac-
teria's outer membrane, forming aggregates and to provoke perfora-
tions, leading to the loss of membrane integrity [88]. Ag ions also
interact with the disulfide or sulfhydryl groups present in the enzyme
structure, causing metabolic process disruption and cell death [89].
Interestingly, Pal et al. found that AgNPs interaction with *Escherichia coli*
may be shape-dependent, with truncated triangular nanoplates having
increased activity compared to spherical or rod-shaped particles [90].

Zn and ZnO-based nanoparticles (ZnONP) have also been extensively studied for their antimicrobial activities [91]. ZnONPs antibacterial mechanisms have been linked to ZnO interactions with functional groups in proteins and nucleic acids inside the bacteria, releasing Zn²⁺ ions that prevent enzyme activity and normal physiological activity [92,93]. Similar to AgNPs, ZnONPs have been shown to bind and destabilize bacterial cell membranes, causing cytosol leakage [94]. Several groups have also tested the co-administration of metal-based nanoparticles and antibiotics to fight antimicrobial resistance [95]. When testing the combination of AgNPs with five conventional antibiotics (imipenem, ciprofloxacin, gentamycin, vancomycin, and trimethoprim) against eight multidrug-resistant bacterial species, Naqvi et al. demonstrated that all antibiotics presented an increased efficacy when delivered in combination with the nanoparticles [96]. These results were corroborated by Iram et al., who showed that vancomycin efficacy against the clinical isolates of vancomycin-resistant *enterococci* was significantly improved through its combination with ZnONPs [97]. Similarly, AgNPs and gold nanoparticles functionalization with ampicillin led to synergistic antibacterial effects against multi-resistant strains *Pseudomonas aeruginosa*, *Enterobacter aerogenes*, and *Staphylococcus aureus* [98]. Although no study has definitively proved any immediate impacts on human health or the environment by metallic nanomaterial-containing products [99], caution and further research are needed, particularly on potential cytotoxic or pro-inflammatory interactions between those nanoparticles and immune cells.

<figure><img src="image_5.png" /><figcaption>Fig. 2. Mechanism of action of nanoparticles suggested against bacteria.</figcaption></figure>
## 2.2. Blood cleansing

### 2.2.1. Magnetic nanoparticles for blood cleansing

In addition to anti-microbial strategies, mechanical cleansing of sepsis-causing compounds, such as pathogen residues and released toxins from the bloodstream, has been explored as a potential intervention to improve sepsis clinical outcomes. The general blood cleansing approach is based on using magnetic nanoparticles (MNP) on which a ligand able to capture pathogen agents is grafted. The MNP/agent complex is then removed via magnetic separation (Fig. 3). Due to their small size and high surface-to-volume ratio, MNPs constitute a potent matrix with a strong binding efficiency toward high molecular weight compounds [100].

One of the first uses of this technology in microbiology was carried out in the early 2010s by Herrmann et al., who used this technology ex vivo to cleanse human whole blood samples spiked with LPS [101]. Using polymyxin B-functionalized CoFe-nanoparticles, the authors were able to reduce the level of LPS in the blood and obtained an attenuated chemotactic activity. Similarly, Kang et al. developed magnetic nanoparticles coated with the carbohydrate-recognition domain of human mannose-binding lectin to capture LPS and whole Gram-negative and Gram-positive bacteria and fungi [102]. Using those nanoparticles and an extracorporeal magnetic microfluidic setup, more than 90% of germs were removed from the blood of living rats pre-infected with *Staphylococcus aureus* or *Escherichia coli*. Through the reduction of the infection, this method also reduced the blood levels of inflammatory cytokines and immune cell infiltration in the lungs and spleen. As this specific cleansing method is independent of the pathogen strain, the authors postulated that this strategy could be helpful in the first hours at the hospital, while blood cultures have not yet identified the pathogen agents. As several clinical trials and meta-analyses have failed to report benefits [103,104], the use of blood cleansing in sepsis therapies has remained in question [105,106], and new studies are currently being carried out focusing on improving patient selection, treatment timing, and monitoring [107]. Thus, the use of nanoparticles may offer new interesting prospects.

### 2.2.2. Nanoparticle-based platforms for blood cleansing

While studying the anti-inflammatory and anti-coagulant effect of High-Density Lipoprotein (HDL) in response to an endotoxin challenge in humans, Birjmohun et al. showed that a low HDL level in healthy males is associated with an increased sensitivity toward inflammatory stimuli compared to normal/high levels [108]. Interestingly, HDL's role in inflammation reduction may be explained by two distinct mechanisms: HDL's direct binding and neutralization of endotoxins, and a debated anti-inflammatory activity through the presence of Apolipoprotein A-I on its surface [109]. In another study in which HDL was

functionalized by incorporating monosialoganglioside GM1 (a glycolipid receptor displaying a high interaction with cholera toxins), Bri-carello et al. demonstrated in vitro that the HDL-GM1 binds to *Cholerae* toxins with high affinity, decreasing the toxin's interaction with cells [110]. Interestingly, Henry et al. demonstrated that sphingomyelin liposomes and sphingomyelin/cholesterol liposomes with a high (66%) cholesterol ratio were also able to bind to a membrane-damaging bacterial toxins. Furthermore, administration of those empty liposomes was shown to improve the efficacy of antibiotic treatment (vancomycin/penicillin) in *Staphylococcus aureus* and *Staphylococcus pneumoniae* murine sepsis models [111]. This strategy was then clinically tested, in a phase 1 study, in combination with a standard antibiotherapy to intensive care patients with severe community-acquired pneumococcal pneumonia (NCT02583373). Data obtained showed that the liposomes were well tolerated [112] and that the treatment led to a faster resolution of organ dysfunction and dysregulated inflammation, leading to shorter stays in intensive care units. Those liposomes are currently being tested in an ongoing phase 2 trial with an expected end in 2026 (NCT05776004).

Another detoxifying strategy recently explored has been the toxin absorbance capacity of the red blood cell (RBC) membrane [113]. By using an extrusion approach, Zhang et al. produced biomimetic nanoparticles by covering a poly-lactic-co-glycolic acid (PLGA) core with RBC membranes. In these studies, RBC-mimicking nanoparticles neutralized α-toxins more efficiently than plain liposomes, preventing the hemolysis of murine RBCs [114,115]. In other studies, the authors applied the same strategy using membrane fragments derived from neutrophils [116] or macrophages [117]. In addition to neutralizing endotoxins, the macrophage-mimicking nanoparticles were shown to sequester pro-inflammatory cytokines, thus inhibiting the inflammatory cascade and improving mice survival in an *Escherichia coli* injection sepsis model [117].

As well as toxins and polysaccharides, proteins and free nucleic acids in blood have also been shown to trigger immune responses [118,119]. Furthermore, the possibility of using cell-free plasma DNA (cfDNA) as a predictive parameter of clinical prognosis in septic patients has been proposed recently [120]. Consequently, Dawulieti et al. developed polyethyleneimine (PEI)-based mesoporous silica nanoparticles with different charge densities of cfDNA scavenger molecules (mainly cationic polymers) and investigated their efficacy on a cecal ligation and puncture (CLP)-induced sepsis model. Repeated intraperitoneal administrations of the PEI nanoparticles led to a significantly higher survival rate (60% compared to 0% for non-treated). Moreover, the PEI nanoparticles also reduced the leukocyte infiltration and tissue damage in the heart, kidneys, liver, and lungs [118]. Another recent study focused on the development of multifunctional tannic acid-Zn2⁺-gentamicin nanoparticles (TA-Zn-Gen NPs) to target multiple

<figure><img src="image_6.png" /><figcaption>Fig. 3. Magnetic nanoparticles for blood purification.</figcaption></figure>
mediators of sepsis. This nanoparticle system exhibited no less than five distinct anti-sepsis activities: scavenging cfDNA, inhibiting TLR activation, reducing ROS, inhibiting macrophage recruitment, and demonstrating potent antibacterial activity. In a CLP-induced sepsis model, TA-Zn-Gen NPs were shown to significantly improve clinical scores, delay lethality, and enhance the survival rate up to 60% [121]. All together, these recent studies show how nanoparticles convey new physical characteristics (3D volume, ligand multivalency or interaction with magnetism) that could be pivotal to developing potent binding approaches to treat sepsis.

## 2.3. Modulating hyperinflammation

Over the last decades, several novel immunomodulatory strategies have been thoroughly investigated to better control excessive inflammation. These include immune receptor (TLR4, CD28) inhibitors [123–125] and various anti-inflammatory drugs such as glucocorticoids [126] and statins [127,128]. The concomitance of both hyperinflammation and hypoinflammation phases within a very short time frame has been identified as the main challenge toward using immunomodulatory drugs [30,31,129]. Hence, Hotchkiss, Monneret, and others have emphasized that while broad anti-inflammatory therapies reduce early mortality, their untargeted effects may exacerbate the immune suppressive phase and increase late mortality [129]. Based on this recent paradigm shift, we believe that effective anti-inflammatory therapeutic strategies in sepsis need to feature two key characteristics: 1) a rapid effect and 2) a high selectivity toward systemic inflammation to protect the integrity of the immune system needed to fight the infection.

The intricacy of the immune system's operations is genuinely remarkable. It consists of a complex network involving various cell types and subtypes that work together to orchestrate the combined efforts of the innate and adaptive immune responses. These cells coordinate their actions, using different signaling molecules, against potential threats while maintaining a balanced response against self-antigens to prevent autoimmune disorders. Given the complexity of the immune system, numerous exciting opportunities exist for leveraging nanotechnology in immunomodulation. Nanoparticle-based approaches have recently been intensively developed to modulate the immune response in rheumatoid arthritis, inflammatory bowel disease, transplantation and atherosclerosis [29,36,130–132]. Similarly, several studies have been carried out in the last few years to target specific immune cells in sepsis (Table 3). In the subsequent sections, we will present key cell-specific nanoparticle-based approaches for combating inflammation in sepsis.

### 2.3.1. Modulating endothelial cells

During acute inflammation, endothelial cells exhibit phenotype changes to favor the binding and extravasation of leukocytes to infected or damaged tissue [133]. Those phenotype changes include the over-expression of leukocyte adhesion molecules such as E, P, and L-selectins and Intercellular Adhesion Molecule-1 (ICAM-1) that allow circulating leukocytes to “roll” on the vascular endothelium under the effect of chemokines and before migrating to the site of inflammation [134]. Following this observation, various teams have designed nanoparticles that target the altered endothelial environment. Sakhalkar et al. demonstrated the ability of PLGA and poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) nanoparticles coated with biotinylated antibodies against selectins VCAM-1 and ICAM-1 to exhibit selective adhesion toward injured endothelium both *in vitro* and in an *in vivo* trauma model [135]. Those nanoparticles could be used as delivery agents to modulate immune cells recruitment and prevent blood clot formation during sepsis. Similarly, the ability of vascular-targeted carriers to bind to leukocyte adhesion molecules can be exploited to actively control immune cell trafficking during inflammatory processes. Kelley et al. demonstrated that polymeric drug carriers prevent leucocyte adhesion on endothelial cells during inflammation [136]. While three possible

mechanisms were highlighted: “(1) collisions in blood flow that disrupt leukocyte adhesion, (2) specific binding to the endothelium cells that competes with leukocytes for binding sites, and (3) particle phagocytosis that alters leukocyte phenotype”, the authors hypothesized that the latter was the main mechanism.

### 2.3.2. Modulating neutrophils

Neutrophils are a key cell effector of the innate immune response involved in sepsis inflammatory mechanisms [137]. Once activated, neutrophils start forming a network structure containing DNA and proteins, known as the neutrophil extracellular traps (NETs). Those NETs aim to trap invading microorganisms during an infection. However, numerous studies describe the detrimental role of NETs in sepsis. Excessive and systemic NETs formations have been shown to damage the microcirculation and to induce intravascular coagulation as well as platelet activation, facilitating the formation of thromboses [138]. Those findings suggest that uncontrolled recruitment and activation of neutrophils may exacerbate inflammation and accelerate the onset of clinical disorders such as vascular thrombosis during sepsis [139]. As a result, significant research efforts have been made in recent years to develop methods that modulate neutrophil functions. For that purpose, Cruz et al. designed a novel nanoparticle-based platform relying on the use of α1-antitrypsin-derived peptide to enhance the binding specificity to neutrophil elastase, which is exclusively present on the membrane of neutrophils and overexpressed upon their activation. After loading those nanoparticles with hydroxychloroquine, the authors observed *in vitro* a reduction in neutrophil activity while preserving their viability and a subsequent *in vivo* therapeutic effect on murine venous thrombosis, as treated animals presented significantly smaller thrombi compared to control groups [140]. NETs themselves can also be targeted by administering either neutrophil elastase inhibitor or DNAse through nanocarriers [141]. Another interesting strategy focuses on neutrophils/monocytes hitchhiking [142] to deliver nanoparticles to the inflamed sites. Three recent studies, including one from our laboratory, explored this strategy, using either micelles, liposomes or protein-based nanoparticles to deliver dexamethasone, leading to potent effects *in vitro* and *in vivo* on both neutrophils and macrophages/monocytes populations [143–145].

### 2.3.3. Modulating monocytes/macrophages

Monocytes and macrophages actively participate in intricate immune responses during sepsis, influencing the course of the syndrome by interacting with inflammatory mediators and pathogens. Their ability to both trigger and modulate the inflammatory cascade makes them key players in the complex pathogenesis of sepsis and attractive cellular targets. Casey et al. investigated the ability of empty PLGA and PLA nanoparticles coated with the anionic surfactant poly(ethylene-alt-maleic acid) to induce a wide range of anti-inflammatory responses in innate immune cells when interacting with TLR. The authors demonstrated that the negative charges of nanoparticles play a key part in inducing the reduction of costimulatory molecule expression and the secretion of cytokines induced by TLR activation [146].

Different research groups have investigated other strategies involving anti-inflammatory mechanisms in monocytes and macrophages. Lu et al. for example, tested an HDL-mimicking peptide-phospholipid scaffold (HPPS) as a delivery system to improve the bioavailability of curcumin [147], a natural polyphenol with antioxidant and anti-inflammatory activity via the modulation of the NF-κB pathway [148]. Curcumin-loaded HPPS were designed to target specifically the monocytes through the scavenger receptor class B type I (SR-B1) receptor. The subsequent use of those nanoparticles in an experimental autoimmune encephalomyelitis mouse (EAE) model showed a decrease in inflammatory monocyte trafficking through the brain-blood barrier and other effector immune cells, leading to the reduction of EAE morbidity [147]. Similarly, Xu X. et al. developed astragalus polysaccharide-based nanoparticles that can bind to TLR4 receptors and
<table><caption>**Table 3**
Examples of nanoparticle-based approaches to target different cell effectors.</caption><thead><tr><th>Targeted cell</th><th>Material</th><th>Targeting strategy and mechanism</th><th>Key results</th><th>Study model</th><th>References</th></tr></thead><tbody><tr><td>Endothelial cells</td><td>PLA-PEG nanoparticles</td><td>PLA-PEG particles conjugated with mAbs to target E-selectin, VCAM-1, or ICAM-1</td><td><b>In vitro</b>: Particles exhibit up to 15-fold higher adhesion to inflamed endothelium, compared to non-inflamed endothelium<br><b>In vivo</b>: 6-fold higher adhesion to cytokine-inflamed endothelium relative to non-cytokine-treated endothelium and 10-fold enhancement in adhesion to trauma-induced inflamed endothelium</td><td><b>In vitro</b>: HUVEC activated for 4 h with IL-1β and TNF-α within a plate flow chamber<br><b>In vivo</b>: Trauma model by pinning the muscle or TNF-α model by administering TNF-α</td><td>[135]</td></tr><tr><td>Endothelial cells</td><td>Polystyrene nanoparticles</td><td>Polystyrene nanoparticles were decorated with Sialyl Lewis A to target E-selectin to compete with leukocytes for binding sites</td><td><b>In vitro</b>: Drastic reduction in leucocytes adhesion correlated to nanoparticles concentration<br>When combined with hydroxychloroquine</td><td><b>In vitro</b>: HUVEC cultured on glass coverslips and activated for 4 h with IL-1β.</td><td>[136]</td></tr><tr><td>Neutrophils</td><td>DSPC<br>Cholesterol<br>DSPE-PEG2000-Mal</td><td>α1-antitrypsin-derived peptide to bind neutrophils elastase</td><td><b>In vitro</b>: Significant reduction of neutrophil activities<br><b>In vivo</b>: Therapeutic effect on a murine venous thrombosis model</td><td><b>In vitro</b>: Wild-type neutrophils and platelets on coverslips<br><b>In vivo</b>: Murine venous thrombosis model</td><td>[140]</td></tr><tr><td>Neutrophils</td><td>PLGA nanoparticles</td><td>PLGA nanoparticles loaded with paclitaxel were mixed with CXCL1 hydrogel to induce a targeted signal to attract an influx of neutrophils</td><td><b>In vivo</b>: PLGA nanoparticles with the CXCL1 hydrogels exhibited superior tumor inhibition capability.</td><td><b>In vivo</b>: Melanoma mouse model</td><td>[142]</td></tr><tr><td>Monocytes/ macrophages</td><td>PLGA-PLA nanoparticles<br>And PLA-PEMA nanoparticles</td><td>Innate downregulation of TLR-induced costimulatory molecule expression and cytokine secretion</td><td><b>In vitro</b>: Inhibition of the secretion of inflammatory cytokines induced by LPS<br><b>In vivo</b>: Increased survival on LPS-induced endotoxemia mouse model</td><td><b>In vitro</b>: RAW 264.7 and BDMCs stimulated with 100 ng/mL of either LPS<br><b>In vivo</b>: LPS-induced endotoxemia mouse model</td><td>[146]</td></tr><tr><td>Monocytes</td><td>High-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS)</td><td>Apoa-1 mimetic peptide (R4F) as targeting moiety toward receptor class B type I (SR-B1) on monocytes and the encapsulation of curcumin to inhibit the activation of the NF-κB pathway</td><td><b>In vitro</b>: 80% of monocytes took up HPPS, which was over 20-fold higher than the percentage of neutrophils that took up HPPS<br><b>In vivo</b>: Curcumin-loaded HPPS decrease the morbidity and inhibit pathological process of EAE mice</td><td><b>In vitro</b>: Monocytes and neutrophils isolated from the bone marrow<br><b>In vivo</b>: Experimental autoimmune encephalomyelitis mouse model</td><td>[147]</td></tr><tr><td>Macrophages</td><td>Superparamagnetic iron oxide nanoparticles</td><td>Induce autophagy and activation of the Caveolin1-Notch1/ HES1 signal pathway<br>Passive targeting due to the natural accumulation of SPIONs NPs in the liver</td><td><b>In vivo</b>: Increased the level of IL-10 in liver macrophages</td><td><b>In vivo</b>: LPS-induced endotoxemia mouse model</td><td>[151]</td></tr><tr><td>Macrophages</td><td>PLGA nanoparticles</td><td>PLGA NPs decorated with di(α2 → 8) N-acetylneuraminic acid (NANA), which mimics sialic acid, the natural ligand for a critical anti-inflammatory receptor found on macrophages (Siglec-E)</td><td><b>In vitro</b>: attenuation of LPS-induced production of the proinflammatory TNF-α and IL-6<br><b>In vivo</b>: LPS systemic inflammation model: increased survival, reduction in serum TNF-α and increased levels of IL-10<br>Lung injury murine model: lung homogenate IL-10 levels were significantly elevated, reduction in BAL fluid total cell counts and neutrophil numbers</td><td><b>In vitro</b>: Peritoneal macrophages stimulated for 12 h with LPS<br><b>In vivo</b>: Murine models of systemic inflammation and lung injury</td><td>[153]</td></tr><tr><td>Hepatocytes</td><td>Liposomes</td><td>Liposome decorated with DY-635 to target organic-anion-transporters</td><td><b>In vivo</b>: Targeted liposomes led to specific liver and kidney distribution avoiding uptake by immune cells. Protection of liver's excretory functions while diminishing immune off-target effects.</td><td>Murine model of peritoneal infection by intraperitoneal injection of human stool</td><td>[154]</td></tr><tr><td>Myocardial tissues</td><td>PLGA nanoparticles</td><td>PLGA nanoparticles were decorated with macrophage membranes</td><td>Reduction of proptosis-related pathways and inflammation in myocardial tissues. Improved cardiac characteristics</td><td>Murine model: prophylactic administration before LPS intraperitoneal injection</td><td>[155]</td></tr><tr><td>Brain endothelial cells</td><td>Lipid nanoparticles</td><td>Lipid nanoparticles conjugated with anti-VCAM1 antibodies</td><td><b>In vivo</b>: 300-fold higher brain/blood ratio than control IgG-NPs. Potent delivery of thrombomodulin mRNA and decrease in vascular leakage</td><td>TNF-α-induced inflammatory murine model</td><td>[156]</td></tr></tbody></table>
modulate TLR4-related NF-κB pathway [149]. As those nanoparticles demonstrated *in vivo* efficacy to improve heart function in an arthritic rat model by improving myocardial antioxidant ability and suppressing inflammation, we believe this strategy could also be employed in sepsis. Alongside TLR-based activation, autophagy is an important innate immune mechanism against microbial threats, with several studies demonstrating the protective effect of autophagy-mediated macrophage regulation against multiple organ damage in murine sepsis models [150]. Xu et al. recently used superparamagnetic iron oxide nanoparticles (SPION) to induce autophagy and activation of the Caveolin1-Notch1/HES1 signal pathway in macrophages [151]. Using an LPS-induced murine sepsis and liver injury model, the authors observed an increase in interleukin-10 (IL-10) level, specifically in liver macrophages, upon treatment with SPIONs. Administration of SPIONs also reduced the infiltration of inflammatory cells into the liver. The protective effects of SPIONs were significantly diminished in mice lacking IL-10 or when autophagy was inhibited.

Nicotinamide adenine dinucleotide (NAD) is a coenzyme involved in various metabolic pathways such as oxidative phosphorylation and ATP production. Interestingly, Ye et al. demonstrated that incubating LPS-activated macrophages with NAD-loaded lipid nanoparticles not only led to a decrease in the production of pro-inflammatory cytokines and oxidative species by the cells but also improved their viability. *In vivo*, intravenous administration of those NPs in an LPS-murine model led to a reduction of blood cellular and molecular makers, and significantly improved the survival of the treated animals. The NPs also accumulated in the mice' liver, lungs and kidneys where they stimulated the recovery of the ATP levels and the reduction of organ and tissue damage. Finally, the authors revealed that in a CLP model, NAD-loaded lipid nanoparticles treatment not only improved short term survival, but also led to significantly reduce the mortality of a secondary *Pseudomonas aeruginosa* lung infection [152]. Another promising strategy is based on sialic acid-binding immunoglobulin lectin (Siglec), which are immunomodulatory receptors expressed predominantly on the surface of hematopoietic cells. Spence et al. showed that nanoparticles functionalized with a sialic acid derivative, N-acetyl Neuraminic Acid (NANA), were able to cross-link those Siglec receptors and significantly attenuated LPS-induced TNF-α and IL-6 secretion *in vitro* (on peritoneal macrophages activated with LPS) and *in vivo* (on a lung injury mouse model) [153]. Importantly, the authors demonstrated the applicability of their strategies in a murine CLP model and in a human *ex vivo* lung perfusion model pre-instilled with LPS.

### 2.3.4. Control of reactive oxygen and nitrogen species

Reactive oxygen and nitrogen species (RONS) are involved in various biochemical processes, including signal transmission, metabolic and inflammatory modulation [157]. During sepsis, RONS are overproduced and are poorly scavenged by the immune system. Thereafter, high levels of RONS can damage cells, impairing the immune system and tissues, eventually leading to multiple organ failure syndrome [158]. Unfortunately, the use of conventional antioxidants such as vitamin C or N-acetylcysteine has failed to improve outcomes in sepsis [159,160].

The application of nanomaterials such as RONS scavengers has drawn much interest in recent years, mainly using inorganic metal nanomaterials which can convert peroxides to H₂O and O₂. For example, cerium-based nanoparticles are characterized by the Ce⁴⁺ and Ce³⁺ redox pair that cohabits on their surface. As such, those nanoparticles can scavenge free radicals *via* reversibly binding oxygen and the surface transition of Ce³⁺ to Ce⁴⁺. As monocytes are prone to internalize cerium-based nanoparticles, this approach can be used to lower intracellular RONS levels, especially when monocytes are stimulated [161]. Indeed, administration of cerium-zirconium nanoparticles has been shown to effectively reduce systemic inflammation and mortality in a CLP-induced mouse model and an LPS-induced endotoxemia rat model [162].

Similarly to endotoxin-scavenging strategies presented earlier,

nanoparticles can also be used to interact and sequester RONS directly [163]. For example, an infusion fluid composed of a mixture of egg lecithin and soybean oil lipids that form micelles and liposomes [164] have been tested in a phase 2a clinical trial to treat septic shock patients with hypovolemia (NCT04257136). The treatment led to an elevation of blood pressure in the patient with improved signs of organ function and reduction of inflammation features [122]. While the exact mechanisms of action over the RONS capture could not be proved in this trial, a new Phase 3 study has been initiated in 2024 (NCT06072430).

Various compounds with distinct RONS-scavenging properties [165], such as redox polymers [166], scavenging enzymes [119], and melanins [167], have also been tested to modulate RONS response. Melanin-based nanoparticles, for instance, were tested in a rat model of ischemic stroke, and their administration led to a significantly lower infarction area than in the saline-treated group [149]. Another strategy focused on bilirubin, a byproduct resulting from heme metabolism, to modulate the redox-sensitive transcription factor hypoxia-inducible factor-1 (HIF-1) and to prevent NADPH oxidase-related RONS generation and TLR4-mediated LPS inflammatory response. PEG-conjugated bilirubin nanoparticles effectively attenuated the manifestations of pulmonary fibrosis in a mouse pulmonary fibrosis model without notable adverse effects [168]. When compared to the saline-treated control group, animals treated with bilirubin presented not only lower RONS and cytokine levels but also significantly lower neutrophil infiltration, macrophage activation, and differentiation of epithelial cells/fibroblasts into myofibroblasts. However, the clinical relevance of these findings in managing sepsis remains uncertain. Elevated bilirubin levels in critically ill patients often indicate underlying pathologies and may not reflect a beneficial response.

### 2.4. Fighting sepsis-induced immunosuppression

As described in the first part of this review, recent clinical data show that a substantial proportion of septic patients who have survived the initial inflammatory storm rapidly progress to an immunosuppressive state. This immune cell paralysis results in an inability to clear invading microorganisms that increases patient susceptibility to secondary infections, including hospital-acquired ones, and may increase the mortality rate [129,169]. Consequently, several teams have recently focused on restoring the patient's immune system activity through administration of immunostimulatory agents [170,171] such as GM-CSF [172], IL-17 [173], IFNγ [174], and PD-1/PD-L1 inhibitors [175,176]. Unfortunately, the majority of those studies have failed to demonstrate significant survival benefits [31,32].

Although those immunostimulatory agents have considerable potential, their delivery in a sepsis setting may often face inferior pharmacokinetic properties due to biodegradability and impaired targeting. As such, these compounds could substantially benefit from the use of nanoparticle delivery platforms. Interestingly, several nanoparticle-based immunostimulatory strategies have already been applied to sepsis. For instance, SPIONs have been conjugated to β-glucan to generate innate immune memory, also called “trained immunity”, in order to fight secondary infections. Those β-glucan-SPIONs were administered twice in mice between two intraperitoneal injections with *Escherichia coli*. Results showed that this β-glucan-SPION regimen enhanced peritoneal macrophages recovery after the primary infection, resulting in a subsequent higher bacteria clearance rate and a decrease in lung and liver injuries after the second infection [177]. Schrijver et al. also explored this promising approach of using trained immunity to reverse sepsis-induced immunoparalysis. The authors revealed that interleukin-4 (IL-4) can simultaneously suppress acute inflammation and induce trained immunity in cultured human primary monocytes. By using lipidic nanoparticles bearing an Apolipoprotein-A1-IL-4 conjugate, the authors showed the ability of these nanoparticles to target myeloid-cell-rich hematopoietic organs in experimental models, and that IL-4 delivery effectively resolved immunoparalysis, offering
promising prospects for sepsis treatment [178].

## 2.5. Organ-targeted nanostrategies

### 2.5.1. Targeting sepsis-induced acute liver injury

As the dysregulated host responses described above may trigger multiple organ dysfunction, various laboratories have developed organ-targeted strategies using nanoparticles. With an incidence around 40%, hepatic dysfunction is a common early adverse consequence of the dysregulated host response [179]. Sepsis-induced acute liver injury (SILI) can be triggered by several intertwined mechanisms, including systemic inflammation, liver inflammation, metabolic dysregulation, cell death, and microcirculatory abnormalities, and is associated with further complications and an increased mortality rate [179,180]. Therefore, various laboratories have developed liver-centered strategies, including anti-inflammatory, antioxidant, metabolic, and anti-cell death therapies, including nanostrategies [181–184]. For example, Chen Y. et al. tested poly(ethylene glycol)-poly(propylene sulfide)-based nanoparticles to deliver melatonin to the liver. Results obtained in an LPS-murine model revealed that the prophylactic intraperitoneal administration of melatonin-NPs induced a significant decrease in LPS-induced liver oxidation, proinflammatory cytokines, and NLRP3 inflammasome activation compared to both saline and free melatonin controls [185]. In another study, Press et al. developed a hepatocytes-targeted liposomal platform to specifically deliver a phosphoinositide 3-kinase-γ inhibitor as this kinase plays a pivotal deleterious role during liver failure, but also has a critical role in neutrophils’ protective activity elsewhere [154]. *In vivo* results, obtained in a murine model of intraperitoneal injection of human stools, revealed that while intravenous administration of free PI3Kγ inhibitor provoked an unwanted amplified and prolonged systemic inflammation leading to high mortality, the liver-specific nanodelivery of the molecule led to protection of the liver’s excretory functions and improved outcomes. The authors explained those opposing results by the difference in biodistribution. Indeed, distribution data showed that while the free inhibitor was present in all tissues, the same molecule administered *via* NPs was only measured in the liver and kidneys. These results demonstrate once again how selective delivery using NPs can significantly improve the therapeutic index of various molecules.

### 2.5.2. Targeting sepsis-associated acute kidney injury

Similar to SILI, sepsis-associated acute kidney injury (SA-AKI) has been linked to systemic inflammatory response, tissue inflammation, cellular metabolic changes, and microcirculatory dysfunction [186]. Typically, SA-AKI occurs within a few days of sepsis onset and has been associated with longer hospital stays, higher mortality rates, and reduced quality of life for survivors. Various broad anti-inflammatory, anti-coagulant strategies [187], as well as more specific alkaline phosphatase treatments [188] have been tested to prevent kidney dysfunctions. Additionally, several laboratories have been working on nanoparticle-based strategies to treat sepsis-related AKI [189]. Liu et al. developed small (10–20 nm) micelles composed of platinum and honokiol, a traditional antioxidant Eastern medicine compound. Results obtained in mice demonstrated that intravenous injection of the micelles, 16 h after LPS administration, led to a significant decrease in serum creatinine (CREA) and blood urea nitrogen (BUN) levels indicative of improved kidney function. Furthermore, histopathology and *ex vivo* cellular analyses revealed that the kidneys of treated animals presented a significantly smaller amount of injury features such as damaged renal tubules, tubular epithelial cell detachment, and tubular dilatation [190]. Another small nanoplatform composed of a 2 nm-by-4 nm DNA origami nanostructure coated with IL-10 protein was developed by Li et al. to passively accumulate in the liver and the kidneys. Similarly, intravenous injection of these NPs, 2 h post LPS-injection, led to the reduction of both kidney and liver injuries’ blood makers (CREA/BUN and AST/ALT, respectively), as well as a decrease in tubular injury score

[191].

### 2.5.3. Targeting Sepsis-induced cardiac dysfunctions

Dysregulated systemic inflammation also affects cellular metabolism and homeostasis in the heart, leading to life-threatening cardiac deficiencies such as impaired contractility and diastolic dysfunction, as well as reduced cardiac index and ejection fraction. Similarly to other organs, several studies have demonstrated that nanostrategies can be used to reduce ROS production and inflammation in cardiac tissue [192–194]. In one of them, Li et al. developed PLGA nanoparticles coated with macrophage membranes to deliver a pyroptosis inhibitor into cardiac tissue. *In vivo* experiments in an LPS-murine model revealed that the prophylactic administration of these NPs reduced pyroptosis-related pathways and inflammation in myocardial tissues. Furthermore, echocardiography measurements revealed that mice pretreated with the nanoparticles presented significantly higher ejection fraction and fractional shortening cardiac characteristics compared to free drug-treated animals, indicative of a better myocardial recovery [155].

### 2.5.4. Targeting sepsis-associated encephalopathy

Sepsis systemic inflammatory response can also provoke neuro-inflammation, blood-brain barrier dysfunction, and cerebral ischemia leading to brain injury referred to as sepsis-associated encephalopathy (SAE) [195]. Those disorders, which affect up to 70 % of patients with severe systemic infection [196], can cause impairment of consciousness, delirium, and coma. While no specific treatments exist for SAE, several strategies such as the use of edaravone or resveratrol have been tested to reduce oxidative stress in the brain [197]. Similarly, various NPs have been developed to target and treat the inflamed cerebral vasculature. Marcos-Contreras et al. demonstrated that conjugating anti-VCAM1 antibodies to the surface of lipid nanoparticles led to their accumulation in the inflamed brain endothelium. Using those nanoparticles in a TNF-α-induced inflammatory murine model to deliver thrombomodulin mRNA, the authors observed a significant decrease in vascular albumin leakage, indicative of the reduction in brain edema [156]. In another study, citrate-conjugated gold nanoparticles were tested to prevent leukocyte platelet adhesion in cerebral vessels in a murine CLP model. Results showed that while administration of the nanoparticles did not impact the survival rate, gold nanoparticles treatment led to the reduction of CAM-1 expression in both leukocytes and cerebral blood endothelium, to lower blood-brain barrier permeability, and to decreased TNF-α concentration in the brain parenchyma [198]. In a similar fashion, gold nanoparticles were conjugated to hexapeptides known to inhibit TLR4 signaling pathway. Data revealed that intraperitoneal administration of those NPs led to reduced systemic activation and protective effects on brain function in both LPS and CLP mice models. Furthermore, local brain injections of the NPs 30 min after LPS challenge induced a decrease in microglia compared to saline-treated controls [199]. Finally, Qu et al. developed nanoparticular structures formed between tannic acid, Fe3+ ions, and quercetin [200]. Those structures were then coated by extrusion with murine Raw 264.7 macrophages membranes. Administration of the NPs in a CLP model 4 h after surgery led to not only a higher survival rate (>60 %) compared to controls (free molecules and non-coated NPs) but also a decrease in brain microglia inflammatory state. Furthermore, animals treated with those coated NPs show improved learning and memory behavioral results indicative of reduced brain damage.

## 2.6. Multifunctional nanoparticles

As sepsis is characterized by the activation of multiple cellular and molecular inflammatory pathways, various groups have naturally leaned toward developing multifunctional nanoparticles to concomitantly deliver an array of therapeutic molecules that modulate distinctive pathways. Following this paradigm, Zhang et al. developed bioresponsive polymeric micelles loaded with both an antibiotic
(ciprofloxacin) and the anti-inflammatory agent [2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TCPA). The micelles were made of copolymers sensitive to pH and bacterial enzymes to enable drug release within infectious microenvironments. The micelles were also decorated with antibodies against ICAM-1 to target endothelial cells in inflammatory microenvironments. Administration of ciprofloxacin/TPCA-1 loaded micelles targeting ICAM-1 in a *Pseudomonas aeruginosa* infection murine model led to a survival rate of 90% among the treated group compared to 50% for ciprofloxacin/TPCA-1 nanoparticles coated with an isotype antibody control. Additional biological analyses revealed a marked decrease in leukocyte number and inflammatory cytokines in the treated mice [201]. Based on the same rationale, Yang et al. developed PLGA nanoparticles loaded with the broad-spectrum antibiotic Sparfloxacin (SFX) and the anti-inflammatory immunosuppressant Tacrolimus (TAC) [202]. The nanoparticles were decorated with γ3 peptide (NNQKIVNLKEKVAQLEA) that can specifically bind to ICAM-1. The intravenous administration of γ3-decorated SFX/TAC-nanoparticles in a *Pseudomonas aeruginosa* lung infection murine model led to an inhibition of bacterial proliferation compared to non-targeted SFX/TAC-nanoparticles and free SFX/TAC. Another multidrug strategy has been developed by Dormont et al. using nanoparticles produced by conjugating squalene to adenosine, which can act as an immunomodulator, to deliver the antioxidant α-tocopherol together with adenosine, which can act as an immunomodulator. The use of squalene-based nanoparticles in an LPS endotoxemia model significantly increased drug protection from early degradation as well as their accumulation in inflamed lungs and liver. Nanoparticles administration also improved the survival rate and the clinical scores of the animals [203]. In another study, Li et al. synthesized nanoparticles based on tannic acid, polymyxin B, and Mn2+ to scavenge different inflammatory mediators of sepsis. Tannic acid was chosen for its ability to form stable complexes with DNA, which could help remove harmful reactive oxygen species and cell-free DNA (cfDNA), while polymyxin B was employed for its antimicrobial properties and its capacity to adsorb lipopolysaccharides. The addition of Mn2+ increased the stability of the material. Results obtained on a CLP model demonstrated an increase in survival rate as well as a significant reduction in high ROS levels within the peritoneal cavity after treatment. Furthermore, treated mice exhibited decreased immune cells, reduced macrophage activation, and lower cytokine levels in both the peritoneal cavity and blood [204]. These various studies and the promising results obtained indicate that the precise co-delivery of drug combinations within the infectious microenvironments may be a potent strategy. Though, those combinations need to be carefully studied to avoid any unforeseen effects.

### 3. Nanoparticles for nucleic acid delivery: A new opportunity to treat sepsis

Nucleic acid-based therapies have been booming in recent years thanks to the development of ionizable lipids that allow the formulation of nanoparticles that can simultaneously be administered *in vivo* and provide an efficient endosomal escape [205]. Following the clinical and commercial successes of Onpattro™ (Alnylam Pharmaceuticals) and the messenger RNA vaccines Comirnaty™ (Pfizer & BioNTech) and Spikevax™ (Moderna), nucleic acid-based therapeutic strategies have experienced extraordinary enthusiasm [206]. Due to their ability to theoretically reduce the expression of any gene, strategies based on the administration of interfering RNAs such as antisense oligonucleotides, small interfering RNAs, or microRNAs can help modulate the expression of virtually any genes [207]. In sepsis, nucleic acid-based therapy can be used for different strategies, such as reducing inflammation, producing engineered immune cells, or reducing immunosuppression. While we could have presented those applications earlier in the corresponding chronopathophysiological sections, we have chosen to stress the versatility of nucleic acid-based therapies and describe them based on nucleic acid classes.

#### 3.1. Delivering miRNA

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that play significant roles in a wide range of biological functions. For example, miR-155 has been shown to be upregulated by the administration of LPS and to possess pro-inflammatory activity in numerous cell types and organs. Wang et al. demonstrated that pharmacological inhibition of miR-155 using an antagonist reduced cardiac apoptosis in LPS-treated mice, while over-expression of miR-155 had the opposite effect. Additionally, miR-155 was shown to be elevated in the plasma of patients with septic cardiac dysfunction [208]. In another interesting study, Alexander et al. confirmed the role of miR-155 as a promoter of inflammatory responses, while showing that miR-146a acts as a mediator of immune suppression. After being administered with LPS, mice that received miR-146a-containing exosomes displayed lower TNF-α and IL-6 serum concentrations compared with mice exposed to miR-146a-deficient exosomes [209]. Similarly, Bobba et al., demonstrated that miR-146a could be effectively delivered by intratracheal instillation of cationic lipid-based nanoparticles, leading to significant decreases in lung inflammation and alveolar-capillary permeability [210]. A similar approach has been tested with miR-223 using nanoparticles composed of cyclodextrin and PEGylated phospholipid [211]. The *in vivo* experiments in CLP mice demonstrated the remarkable ability of NPs/miR-223 to accumulate within sites of inflammation and significantly reduce the secretion of inflammatory factors such as IL-1β, TNF-α, and IL-6. Another interesting study led by Li et al. explored the role of tumor-derived exosomes in mitigating sepsis [212]. This study was motivated by a lower incidence of sepsis observed in melanoma patients. In their study, the authors revealed that tumor-bearing mice exhibited increased resistance to LPS-induced sepsis. Further analyses exposed the protective effect of induced exosomes secreted by tumor cells following LPS challenge in mice and cynomolgus monkeys.

#### 3.2. Delivering SiRNA

Small interfering RNAs (siRNA) also display similar translational applications thanks to their ability to inhibit specifically a gene of interest, with several recent studies demonstrating the efficacy of siRNA in animal models of infectious diseases, including sepsis [213–215]. For example, Brahmamdam et al. developed transferrin receptor-targeted nanoparticles to co-administer siRNA against Bim and PUMA, two key cell death proteins, which are markedly upregulated during sepsis. Compared to untreated septic mice, animals treated with both siRNAs loaded in nanoparticles showed reduced levels of both proteins in splenic T cells [216]. Similarly, Lee et al. described the design and synthesis of a nanoparticle-based delivery system capable of efficiently delivering small interfering RNA (siRNA) against TNF-α specifically to macrophages. The nanoparticles were engineered to exhibit on their surface the (Thr-Lys-Pro-Arg) peptide sequence that is known to specifically bind to the neuropilin-1 (NRP-1) receptor. Using those nanoparticles, the authors observed a significant reduction in TNF-α production and an attenuation of the inflammatory response in a CLP model, leading to improved survival rates and the alleviation of sepsis symptoms [217].

#### 3.3. Delivering mRNA

Recently, the therapeutic application of mRNA has also generated significant optimism for addressing a broad spectrum of diseases [218]. The extensive analysis of gene expression datasets has led to the identification of potential targets. For instance, Van den Akker et al. showed that during sepsis, neutrophils exhibit decreased levels of glucocorticoid receptor mRNA [219]. In such cases, the application of mRNA lipid nanoparticles coding for this receptor could potentially enhance the effectiveness of glucocorticoids in sepsis patients. A strategy tested has been the use of vitamin-conjugated lipid nanoparticles to deliver *ex vivo*
mRNA to autologous macrophages. Hou et al. demonstrated that transfecting bone marrow-derived macrophages with a mRNA coding for a fused construct coding for the anti-microbial peptide IB367 and Cathepsin B (a lysosomal protease) increased the cells' anti-microbial activities [220]. Engineered macrophages were then injected back into the animals to boost the innate immunity system (Fig. 4). In a proof-of-concept in vivo study using a cyclophosphamide-induced immunosuppression mouse model challenged with *Staphylococcus aureus* and *Escherichia coli*, the authors demonstrated that administration of the engineered macrophages led to a potent bacterial elimination and an increase in survival rates (58 % compared to 10 % for non-modified macrophages). Interestingly, a similar effect has been obtained using ultrasound-responsive metallic nanoparticles to activate the macrophages before re-injection.

While this ex vivo cell-engineering strategy, inspired by cancer T cell therapies [221] look promising, one of the main clinical challenges will be to collect autologous macrophages and engineer them ex vivo within a very short time frame, as the therapeutic time window available to treat sepsis is much shorter than for cancer. This is why Tang et al. designed a lipid-based nanoparticle platform to co-deliver in vivo an mRNA coding for the chimeric antigen receptor targeting a surface protein expressed

by *Staphylococcus aureus* and siRNA against caspase-11. Administration of these nanoparticles in an immune-depressed murine model infected with methicillin-resistant *Staphylococcus aureus*, induced an important increase in the numbers of activated macrophages and CD11b + neutrophils present in the spleen, and led to a significant improvement in the survival rate of the treated animals [222]. Based on those results and as the field of nanoparticles for nucleic acids is booming, multiple RNA-based strategies are currently being tested against sepsis and will hopefully lead to much-needed clinical success.

## 4. Specific challenges in the context of sepsis

As described in the introduction, sepsis syndrome encompasses an array of different biological conditions in terms of pathogens involved (fungi, yeast, bacteria), primary tissue infected (lungs, peritoneal, wound), or patient population (age, sex, comorbidities, immune status, and drug responsiveness). This heterogeneity constitutes one of the main challenges toward the development of nanoparticle-based approaches against sepsis [223]. While the efficacy of a specific antimicrobial strategy will understandably be determined by pathogen, the nature of the infection may also impact the use of nanoparticles for

<figure><img src="image_7.png" /><figcaption>**Fig. 4.** The anti-microbial peptide Cathepsin B (AMP-CatB) mRNA is encapsulated in the vitamin-conjugated lipid nanoparticles and delivered to the macrophage where the mRNA is translated in the cytoplasm and then translocated into the lysosomes [220]. The engineered macrophages now expressing AMP in the lysosome are administered to the mice.</figcaption></figure>
immunomodulation. Several studies have indeed shown that the immune intracellular pathways and the receptors expressed by the immune cells are highly dependent on the pathogens involved, as well as the resident tissue infected [224]. Thus, this heterogeneity may hinder the development of broad receptor-dependent active targeting strategies. Furthermore, the main targeted cells, i.e., monocytes/macrophages and neutrophils, exhibit a proven high avidity for nanoparticles. While facilitating the general application of nanoparticle-based immunological strategies, these indiscriminate internalization processes can lead to random drug delivery to leukocytes and may also impede the effectiveness of ligand-based strategies aiming at targeting a particular phenotype to reduce side effects. Therefore, further basic research is needed to decipher the influence of the physicochemical characteristics of nanoparticles on their interactions with leukocytes [225,226].

Another challenge is the intertwinement of a pro-inflammatory reaction and an anti-inflammatory response, which complicates the use of broad and anti-inflammatory nanoparticle-based strategies. However, with a large proportion of intubated sepsis patients, we believe that the development of nanoparticle-based approaches allowing local delivery of the treatments, especially in lungs [225], could provide a great opportunity. Additionally, nanoparticles can be used to deliver highly specific therapeutics such as mTOR inhibitor [227] or gene-specific siRNA [207] that may tackle inflammation without inducing immunosuppression. Nanoparticles could also be used to co-deliver immunomodulatory drugs using specific synergistic combinations to reduce the required dose of each molecule and minimize their side effects. We believe that those molecular targeted strategies should be associated with the development of companion biomarkers to allow for better patient selection based on their immune status [228] and/or drug sensitivity [229]. As such, the current developments of *in silico* and artificial intelligence-driven approaches will be key to help diagnosis and patient selection toward specific treatments, including nanostrategies [230–232]. Furthermore, the biological effects of the nanoparticles themselves need to be better understood. For instance, ionizable lipids employed for RNA delivery have been shown to induce inflammatory cell activation [233]. Similarly, the immune toxicity observed with some inorganic nanomaterials [234,235] could worsen immunosuppression. Finally, nanoparticles’ physical characteristics and therefore *in vivo* efficacy are highly dependent on production processes that can complicate manufacturing scale up [236].

Similarly, other types of treatments, nanoparticle-based strategies, suffer from the lack of translatability from animal models to humans. Some of the issues are inherent in the predominance of archetypal murine animal models: an immune system that poorly mimics humans, a lack of genetic diversity, and the use of a pathogen-free barrier facility. Furthermore, most of the sepsis models used tend to be over-simplified and do not mimic sepsis heterogeneity [237]. To address those shortfalls, experts have proposed a set of recommendations to improve preclinical studies and enhance their translatability known as the “*Minimum Quality Threshold in Preclinical Sepsis Studies*” [238–241]. Those recommendations include better evaluation of organ dysfunction, as well as the use of fluid resuscitation and antibiotic regimen to better represent the human standard of care. Those are part of the important work produced by both the nanomedicine and the sepsis communities to reflect on and tackle the various challenges toward a better translatability [242,243].

## 5. Conclusion

As presented in this review, the biomedical applications of nanotechnology are subject to incessant expanding research and display a great potential to impact sepsis treatments. Nanoparticles have a unique ability to be designed to target specific cells and offer many possibilities to address the intricate pathophysiology of sepsis. Thus, we strongly believe that by improving antibacterial strategies, enabling fine-tuning drug delivery, optimizing immunomodulation, reducing organ failure,

and enabling the use of RNA-based strategies, nanotechnology could play a pivotal role in the future in mitigating the devastating impact of sepsis.

### CRediT authorship contribution statement

**Younes Louaguenouni:** Writing – original draft, Conceptualization.
**Arnaud Mansart:** Writing – review & editing.
**Djillali Annane:** Writing – review & editing.
**Elias Fattal:** Writing – review & editing, Writing – original draft, Conceptualization.
**François Fay:** Writing – review & editing, Writing – original draft, Supervision, Conceptualization.

### Acknowledgments

YL received a scholarship from the doctoral school: ED Innovation Thérapeutique – Du Fondamental à l’Appliqué [ITFA n. 569]. This work benefited from the support of the project NANOSEPSIS https://anr.fr/Projet-ANR-20-CE18-0019 of the French National Research Agency (ANR). This work was also supported by the national program France 2030 under the supervision of ANR (IHU-SEPSIS, ANR-23-IAHU-0004). Graphical abstract and figures were created using BioRender. Fay, F. (2025).

### Data availability

No data was used for the research described in the article.

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