Numerous types of contemporary antibiotic treatment regimens have become ineffective with the increasing incidence of drug tolerance. As a result, it is pertinent to seek novel and innovative solutions such as antibacterial nanomaterials (NMs) for the prohibition and treatment of hazardous microbial infections. Unlike traditional antibiotics (e.g., penicillin and tetracycline), the unique physicochemical characteristics (e.g., size dependency) of NMs endow them with bacteriostatic and bactericidal potential. However, it is yet difficult to mechanistically predict or decipher the networks of molecular interaction (e.g., between NMs and the biological systems) and the subsequent immune responses. In light of such research gap, this review outlines various mechanisms accountable for the inception of drug tolerance in bacteria. It also delineates the primary factors governing the NMs-induced molecular mechanisms against microbes, specifically drug-resistant bacteria along with the various NM-based mechanisms of antibacterial activity. The review also explores future directions and prospects for NMs in combating drug-resistant bacteria, while addressing challenges to their commercial viability within the healthcare industry.

Sepsis is a disease with high morbidity and mortality, for which effective treatments are lacking. In recent years, microRNAs (miRs) have been shown to regulate numerous biological processes and can function as therapeutic options for various diseases. However, the poor stability and cell entry properties of miRs have greatly limited their clinical application. In this study, we developed a tetrahedral framework nucleic acid (tFNA)-based bioswitchable miR delivery system (BiRDS) to deliver miR-150 for the treatment of sepsis. BiRDS showed anti-inflammatory effects both in vitro and in vivo by regulating the NF-κB and Notch1 pathways. Therefore, this system holds promise as an ideal candidate for tackling systemic inflammation and multiorgan dysfunction in septic patients in the future.

This study explored the development of novel biomimetic tannic acid-based hybrid nanocarriers (HNs) for targeted delivery of ciprofloxacin (CIP-loaded TAH-NPs) against bacterial-induced sepsis. The prepared CIP-loaded TAH-NPs exhibited appropriate physicochemical characteristics and demonstrated biocompatibility and nonhemolytic properties. Computational simulations and microscale thermophoresis studies validated the strong binding affinity of tannic acid (TA) and its nanoformulation to human Toll-like receptor 4, surpassing that of the natural substrate lipopolysaccharide (LPS), suggesting a potential competitive inhibition against LPS-induced inflammatory responses. CIP released from TAH-NPs displayed a sustained release profile over 72 h. The in vitro antibacterial activity studies revealed that CIP-loaded TAH-NPs exhibited enhanced antibacterial efficacy and efflux pump inhibitory activity. Specifically, they showed a 3-fold increase in biofilm eradication activity against MRSA and a 2-fold increase against P. aeruginosa compared to bare CIP. Time-killing assays demonstrated complete bacterial clearance within 8 h of treatment with CIP-loaded TAH-NPs. In vitro DPPH scavenging and anti-inflammatory investigations confirmed the ability of the prepared hybrid nanosystem to neutralize reactive oxygen species (ROS) and modulate LPS-induced inflammatory responses. Collectively, these results suggest that CIP-loaded TAH-NPs may serve as an innovative nanocarrier for the effective and targeted delivery of antibiotics against bacterial-induced sepsis.

Sepsis is a life-threatening syndrome resulting from an imbalanced immune response to severe infections. Despite advances in nanomedicines, effective treatments for sepsis are still lacking. Herein, vancomycin free base (VCM)-loaded dual functionalized biomimetic liposomes based on a novel TLR4-targeting peptide (P3) and hyaluronic acid (HA) (HA-P3-Lipo) were developed to enhance sepsis therapy. The nanocarrier revealed appropriate physicochemical parameters, good stability, and biocompatibility. The release of VCM from HA-P3-Lipo was found to be sustained with 76 % VCM released in 48 h. The biomimicry was elucidated by in silico tools and MST and results confirmed strong binding between the system and TLR4. Furthermore, HA-P3-Lipo revealed 2-fold enhanced antibacterial activity against S. aureus, sustained antibacterial activity against MRSA over 72 h and 5-fold better MRSA biofilm inhibition compared to bare VCM. Bacterial-killing kinetics and flow cytometry confirmed the superiority of HA-P3-Lipo in eliminating MRSA faster than VCM. The in vivo potential of the nanocarrier was elucidated in an MRSA-induced sepsis mice model, and the results confirmed the superiority of HA-P3-Lipo compared to free VCM in eliminating bacteria and down-regulating the proinflammatory markers. Therefore, HA-P3-Lipo exhibits potential as a promising novel multi-functional nanosystem against sepsis and could significantly contribute to the transformation of sepsis therapy.

Sepsis represents a critical medical condition stemming from an imbalanced host immune response to infections, which is linked to a significant burden of disease. Despite substantial efforts in laboratory and clinical research, sepsis remains a prominent contributor to mortality worldwide. Nanotechnology presents innovative opportunities for the advancement of sepsis diagnosis and treatment. Due to their unique properties, including diversity, ease of synthesis, biocompatibility, high specificity, and excellent pharmacological efficacy, peptides hold great potential as part of nanotechnology approaches against sepsis. Herein, we present a comprehensive and up-to-date review of the applications of peptides in nanosystems for combating sepsis, with the potential to expedite diagnosis and enhance management outcomes. Firstly, sepsis pathophysiology, antisepsis drug targets, current modalities in management and diagnosis with their limitations, and the potential of peptides to advance the diagnosis and management of sepsis have been adequately addressed. The applications have been organized into diagnostic or managing applications, with the last one being further sub-organized into nano-delivered bioactive peptides with antimicrobial or anti-inflammatory activity, peptides as targeting moieties on the surface of nanosystems against sepsis, and peptides as nanocarriers for antisepsis agents. The studies have been grouped thematically and discussed, emphasizing the constructed nanosystem, physicochemical properties, and peptide-imparted enhancement in diagnostic and therapeutic efficacy. The strengths, limitations, and research gaps in each section have been elaborated. Finally, current challenges and potential future paths to enhance the use of peptides in nanosystems for combating sepsis have been deliberately spotlighted. This review reaffirms peptides' potential as promising biomaterials within nanotechnology strategies aimed at improving sepsis diagnosis and management.

Critical care medicine in the 21st century has witnessed remarkable advancements that have significantly improved patient outcomes in intensive care units (ICUs). This abstract provides a concise summary of the latest developments in critical care, highlighting key areas of innovation. Recent advancements in critical care include Precision Medicine: Tailoring treatments based on individual patient characteristics, genomics, and biomarkers to enhance the effectiveness of therapies. The objective is to describe the recent advancements in Critical Care Medicine. Telemedicine: The integration of telehealth technologies for remote patient monitoring and consultation, facilitating timely interventions. Artificial intelligence (AI): AI-driven tools for early disease detection, predictive analytics, and treatment optimization, enhancing clinical decision-making. Organ Support: Advanced life support systems, such as Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy provide better organ support. Infection Control: Innovative infection control measures to combat emerging pathogens and reduce healthcare-associated infections. Ventilation Strategies: Precision ventilation modes and lung-protective strategies to minimize ventilator-induced lung injury. Sepsis Management: Early recognition and aggressive management of sepsis with tailored interventions. Patient-Centered Care: A shift towards patient-centered care focusing on psychological and emotional well-being in addition to medical needs. We conducted a thorough literature search on PubMed, EMBASE, and Scopus using our tailored strategy, incorporating keywords such as critical care, telemedicine, and sepsis management. A total of 125 articles meeting our criteria were included for qualitative synthesis. To ensure reliability, we focused only on articles published in the English language within the last two decades, excluding animal studies, in vitro/molecular studies, and non-original data like editorials, letters, protocols, and conference abstracts. These advancements reflect a dynamic landscape in critical care medicine, where technology, research, and patient-centered approaches converge to improve the quality of care and save lives in ICUs. The future of critical care promises even more innovative solutions to meet the evolving challenges of modern medicine.

Gram-negative sepsis has become a substantial and escalating global healthcare challenge due to the growing antibiotic resistance crisis and the sluggish development of new antibiotics. LL-37, a unique Cathelicidin species found in humans, exhibits a wide range of bioactive properties, including direct bactericidal effects, inflammation regulation, and LPS neutralization. KR-12, the smallest yet potent peptide fragment of LL-37, has been modified to create more effective antimicrobials. In this study, we designed two myristoylated derivatives of KR-12, referred to as Myr-KR-12N and Myr-KR-12C. These derivatives displayed remarkable ability to spontaneously assemble into nanoparticles when mixed with deionized water. Myristoylated KR-12 derivatives exhibited broad-spectrum and intensified bactericidal activity by disrupting bacterial cell membranes. In particular, Myr-KR-12N showed superior capability to rescue mice from lethal E. coli-induced sepsis in comparison with the conventional antibiotic meropenem. We also confirmed that the myristoylated KR-12 nanobiotic possesses significant LPS binding capacity and effectively reduces inflammation in vitro. In an in vivo context, Myr-KR-12N outperformed polymyxin B in rescuing mice from LPS-induced sepsis. Crucially, toxicological assessments revealed that neither Myr-KR-12N nor Myr-KR-12C nanobiotics induced meaningful hemolysis or caused damage to the liver and kidneys. Collectively, our study has yielded an innovative nanobiotic with dual capabilities of bactericidal action and LPS-neutralization, offering substantial promise for advancing the clinical translation of antimicrobial peptides and the development of novel antibiotics. This addresses the critical need for effective solutions to combat Gram-negative sepsis, a pressing global medical challenge.

Sepsis-induced acute liver injury is a life-threatening condition involving inflammation, oxidative stress, and endothelial dysfunction. In the present study, the preventive effects of resveratrol (RV) alone and RV-loaded silver nanoparticles (AgNPs + RV) against sepsis-induced damage were investigated and compared in a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Rats were divided into four groups: Sham, CLP, RV, and AgNPs + RV. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, presepsin, procalcitonin (PCT), 8-hydroxy-2'-deoxyguanosine (8-OHDG), vascular endothelial growth factor (VEGF), and sirtuin-1 (SIRT1) levels were assessed to determine the treatments' effects. AgNPs + RV treatment significantly reduced pro-inflammatory cytokines, NF-κB activation, presepsin, PCT, 8-OHDG, and VEGF levels compared with the CLP group, indicating attenuation of sepsis-induced liver injury. Both RV and AgNPs + RV treatments increased SIRT1 levels, suggesting a potential role of SIRT1 activation in mediating the protective effects. In conclusion, AgNPs + RV treatment demonstrated extremely enhanced efficacy in alleviating sepsis-induced liver injury by modulating inflammation, oxidative stress, and endothelial dysfunction, potentially mediated through SIRT1 activation. In this study, the effect of AgNPs + RV on sepsis was evaluated for the first time, and these findings highlight AgNPs + RV as a promising therapeutic strategy for managing sepsis-induced liver injury, warranting further investigation.

Sepsis is a critical disease caused by the abrupt increase of bacteria in human blood, which subsequently causes a cytokine storm. Early identification of bacteria is critical to treating a patient with proper antibiotics to avoid sepsis. However, conventional culture-based identification takes a long time. Polymerase chain reaction (PCR) is not so successful because of the complexity and similarity in the genome sequence of some bacterial species, making it difficult to design primers and thus less suitable for rapid bacterial identification. To address these issues, several new technologies have been developed. Recent advances in nanotechnology have shown great potential for fast and accurate bacterial identification. The most promising strategy in nanotechnology involves the use of nanoparticles, which has led to the advancement of highly specific and sensitive biosensors capable of detecting and identifying bacteria even at low concentrations in very little time. The primary drawback of conventional antibiotics is the potential for antimicrobial resistance, which can lead to the development of superbacteria, making them difficult to treat. The incorporation of diverse nanomaterials and designs of nanomaterials has been utilized to kill bacteria efficiently. Nanomaterials with distinct physicochemical properties, such as optical and magnetic properties, including plasmonic and magnetic nanoparticles, have been extensively studied for their potential to efficiently kill bacteria. In this review, we are emphasizing the recent advances in nano-biotechnologies for bacterial identification and anti-bacterial properties. The basic principles of new technologies, as well as their future challenges, have been discussed.

Sepsis and septic shock are still one of the most important medical challenges. Sepsis is an extreme and uncontrolled response of the innate immune system to invading pathogenesis. Resveratrol (3,5,4'-trihydroxytrans-stilbene), is a phenolic and non-flavonoid compound naturally produced by some plants and fruits. The object of the current study is to systematically review the impacts of resveratrol and its mechanisms of function in the management of sepsis and its related complications. The guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements were applied to perform the study (PROSPERO: CRD42021289357). We searched Embase, Web of Science, Google Scholar, Science Direct, PubMed, ProQuest, and Scopus databases up to January 2023 by using the relevant keywords. Study criteria were met by 72 out of 1415 articles screened. The results of this systematic review depict that resveratrol can reduces the complications of sepsis by affecting inflammatory pathways, oxidative stress, and modulating immune responses. Future human randomized clinical trials are necessary due to the promising therapeutic effects of resveratrol on sepsis complications and the lack of clinical trials in this regard.

Pyroptosis, systemic inflammation, and mitochondrial apoptosis are the three primary contributors to sepsis's multiple organ failure, the ultimate cause of high clinical mortality. Currently, the drugs under development only target a single pathogenesis, which is obviously insufficient. In this study, an acid-responsive hollow mesoporous polydopamine (HMPDA) nanocarrier that is highly capable of carrying both the hydrophilic drug NAD+ and the hydrophobic drug BAPTA-AM, with its outer layer being sealed by the inflammatory targeting peptide PEG-LSA, is developed. Once targeted to the region of inflammation, HMPDA begins depolymerization, releasing the drugs NAD+ and BAPTA-AM. Depletion of polydopamine on excessive reactive oxygen species production, promotion of ATP production and anti-inflammation by NAD+ replenishment, and chelation of BAPTA (generated by BA-AM hydrolysis) on overloaded Ca2+ can comprehensively block the three stages of sepsis, i.e., precisely inhibit the activation of pyroptosis pathway (NF-κB-NLRP3-ASC-Casp-1), inflammation pathway (IL-1β, IL-6, and TNF-α), and mitochondrial apoptosis pathway (Bcl-2/Bax-Cyt-C-Casp-9-Casp-3), thereby restoring intracellular homeostasis, saving the cells in a state of "critical survival," further reducing LPS-induced systemic inflammation, finally restoring the organ functions. In conclusion, the synthesis of this agent provides a simple and effective synergistic drug delivery nanosystem, which demonstrates significant therapeutic potential in a model of LPS-induced sepsis.

The drugs targeting the PD-1/PD-L1 pathway have gained abundant clinical applications for cancer immunotherapy. However, only a part of patients benefit from such immunotherapy. Thus, brilliant novel tactic to increase the response rate of patients is on the agenda. Nanocarriers, particularly the rationally designed intelligent delivery systems with controllable therapeutic agent release ability and improved tumor targeting capacity, are firmly recommended. In light of this, state-of-the-art nanocarriers that are responsive to tumor-specific microenvironments (internal stimuli, including tumor acidic microenvironment, high level of GSH and ROS, specifically upregulated enzymes) or external stimuli (e.g., light, ultrasound, radiation) and release the target immunomodulators at tumor sites feature the advantages of increased anti-tumor potency but decreased off-target toxicity. Given the fantastic past achievements and the rapid developments in this field, the future is promising. In this review, intelligent delivery platforms targeting the PD-1/PD-L1 axis are attentively appraised. Specifically, mechanisms of the action of these stimuli-responsive drug release platforms are summarized to raise some guidelines for prior PD-1/PD-L1-based nanocarrier designs. Finally, the conclusion and outlook in intelligent delivery system targeting PD-1/PD-L1 pathway for cancer immunotherapy are outlined.

Sepsis is a life-threatening disease caused by the dis-functioning of the immune response to pathogenic infections. Despite, the discovery of modern therapeutics and treatments of sepsis are lacking due to the resistance of pathogens. Metronidazole is an antibiotic commonly used to treat bacterial infections, but usage is limited and challenging by a short half-life period. In this research work, fabricate a pH-responsive drug delivery system for controlled release of metronidazole targeted molecules. We exemplified that, the encapsulation of hydrophilic metronidazole drug within a hydrophobic ZIF-90 framework can be enhanced the pH-responsive drug release under acidic conditions. The ZIF-90 frameworks only decompose in under acidic solutions, they are highly stable in physiological conditions. The pH-responsive protonation mechanism of ZIF-90 frameworks promotes the quick release of metronidazole within cells. The antimicrobial proficiency of zinc and metronidazole will expose a synergistic effect in ROS-mediated bacterial inhibition and auto-immunity boosting of normal cells. In vitro, antibacterial activity results revealed that the MI@ZIF-90 nano drug delivery system effectively eradicated human infectious pathogens at the lowest concentrations. In anti-fungal activity, studies show excellent growth inhibition against human pathogenic fungi Aspergillus fumigatus and Candida albicans. Finally, the PBMC cytocompatibility study concludes, that the fabricated MI@ZIF-90 drug delivery system is non-toxic to biomedical applications. The overall research findings highlight the design of a smart drug delivery system for sepsis treatment. In future it will be an efficient, low-cost, and biocompatible pharmaceutics for pediatric sepsis management processes.

Sepsis is a life-threatening organ dysfunction characterized by severe systemic inflammatory response to infection. Effective treatment of bacterial sepsis remains a paramount clinical challenge, due to its astonishingly rapid progression and the prevalence of bacterial drug resistance. Here, we present a decoy nanozyme-enabled intervention strategy for multitarget blockade of proinflammatory cascades to treat multi-drug-resistant (MDR) bacterial sepsis. The decoy nanozymes (named MCeC@MΦ) consist mesoporous silica nanoparticle cores loaded with CeO2 nanocatalyst and Ce6 photosensitizer and biomimetic shells of macrophage membrane. By acting as macrophage decoys, MCeC@MΦ allow targeted photodynamic eradication of MDR bacteria and realize simultaneous endotoxin/proinflammatory cytokine neutralization. Meanwhile, MCeC@MΦ possess intriguing superoxide dismutase and catalase-like activities as well as hydroxyl radical antioxidant capacity and enable catalytic scavenging of multiple reactive oxygen species (ROS). These unique capabilities make MCeC@MΦ to collaboratively address the issues of bacterial infection, endotoxin/proinflammatory cytokine secretion, and ROS burst, fully cutting off the path of proinflammatory cascades to reverse the progression of bacterial sepsis. In vivo experiments demonstrate that MCeC@MΦ considerably attenuate systemic hyperinflammation and rapidly rescue organ damage within 1 day to confer higher survival rates (>75%) to mice with progressive MDR Escherichia coli bacteremia. The proposed decoy nanozyme-enabled multitarget collaborative intervention strategy offers a powerful modality for bacterial sepsis management and opens up possibilities for the treatment of cytokine storm in the COVID-19 pandemic and immune-mediated inflammation diseases.

The global emergence of antimicrobial resistance (AMR) needs no emphasis. In this study, the in vitro stability, safety, and antimicrobial efficacy of nanosilver-entrapped cinnamaldehyde (AgC) against multi-drug-resistant (MDR) strains of enteroaggregative Escherichia coli (EAEC) were investigated. Further, the in vivo antibacterial efficacy of AgC against MDR-EAEC was also assessed in Galleria mellonella larval model. In brief, UV-Vis and Fourier transform infrared (FTIR) spectroscopy confirmed effective entrapment of cinnamaldehyde with nanosilver, and the loading efficiency was estimated to be 29.50 ± 0.56%. The AgC was of crystalline form as determined by the X-ray diffractogram with a mono-dispersed spherical morphology of 9.243 ± 1.83 nm in electron microscopy. AgC exhibited a minimum inhibitory concentration (MIC) of 0.008−0.016 mg/mL and a minimum bactericidal concentration (MBC) of 0.008−0.032 mg/mL against MDR- EAEC strains. Furthermore, AgC was stable (high-end temperatures, proteases, cationic salts, pH, and host sera) and tested safe for sheep erythrocytes as well as secondary cell lines (RAW 264.7 and HEp-2) with no negative effects on the commensal gut lactobacilli. in vitro, time-kill assays revealed that MBC levels of AgC could eliminate MDR-EAEC infection in 120 min. In G. mellonella larvae, AgC (MBC values) increased survival, decreased MDR-EAEC counts (p < 0.001), had an enhanced immunomodulatory effect, and was tested safe to the host. These findings infer that entrapment enhanced the efficacy of cinnamaldehyde and AgNPs, overcoming their limitations when used individually, indicating AgC as a promising alternative antimicrobial candidate. However, further investigation in appropriate animal models is required to declare its application against MDR pathogens.