ExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated (ECMO-RESCUE): study protocol for a prospective, multicentre, non-randomised cohort study.

INTRODUCTION: Severe septic cardiomyopathy (SCM) is one of the main causes of refractory septic shock (RSS), with a high mortality. The application of venoarterial extracorporeal membrane oxygenation (ECMO) to support the impaired cardiac function in patients with septic shock remains controversial. Moreover, no prospective studies have been taken to address whether venoarterial ECMO treatment could improve the outcome of patients with sepsis-induced cardiogenic shock. The objective of this study is to assess whether venoarterial ECMO treatment can improve the 30-day survival rate of patients with sepsis-induced refractory cardiogenic shock. METHODS AND ANALYSIS: ExtraCorporeal Membrane Oxygenation in the therapy for REfractory Septic shock with Cardiac function Under Estimated is a prospective, multicentre, non-randomised, cohort study on the application of ECMO in SCM. At least 64 patients with SCM and RSS will be enrolled in an estimated ratio of 1:1.5. Participants taking venoarterial ECMO during the period of study are referred to as cohort 1, and patients receiving only conventional therapy without ECMO belong to cohort 2. The primary outcome is survival in a 30-day follow-up period. Other end points include survival to intensive care unit (ICU) discharge, hospital survival, 6-month survival, quality of life for long-term survival (EQ-5D score), successful rate of ECMO weaning, long-term survivors' cardiac function, the number of days alive without continuous renal replacement therapy, mechanical ventilation and vasopressor, ICU and hospital length of stay, the rate of complications potentially related to ECMO treatment. ETHICS AND DISSEMINATION: The trial has been approved by the Clinical Research and Application Institutional Review Board of the Second Affiliated Hospital of Guangzhou Medical University (2020-hs-51). Participants will be screened and enrolled from ICU patients with septic shock by clinicians, with no public advertisement for recruitment. Results will be disseminated in research journals and through conference presentations. TRIAL REGISTRATION NUMBER: NCT05184296.

NIR-responsive MoS2-Cu2WS4 nanosheets for catalytic/photothermal therapy of methicillin-resistant Staphylococcus aureus infections.

The extensive usage of antibiotics causes the rapid evolution of drug-resistant bacteria, which seriously threaten human health. Thus, efficient strategies for treating drug-resistant bacterial infections are urgently needed. Herein, MoS2-Cu2WS4 nanosheets (MS-CWS NSs) are prepared as a near-infrared (NIR) light responsive nanozyme to effectively combat methicillin-resistant Staphylococcus aureus (MRSA) infections by catalytic/photothermal effects. By integrating oxidase (OXD)- and peroxidase (POD)-mimic catalytic activity, MS-CWS NSs have the ability to inactivate MRSA without the addition of H2O2. Moreover, the reactive oxygen species (ROS) produced from MS-CWS NSs are further enhanced by NIR light irradiation, which remarkably causes the death of MRSA. MS-CWS NSs show 4.4 log (99.996%) bacterial inactivation efficiency of MRSA in vitro under NIR light irradiation (0.8 W cm-2, 5 min). In an MRSA infected wound mouse model, MS-CWS NSs inactivate the MRSA by more than 5.2 log (>99.999%) and effectively promote wound healing. This work provides an NIR-responsive 2D nanozyme for efficient treatment of MRSA infections.

A multifunctional Fenton nanoagent for microenvironment-selective anti-biofilm and anti-inflammatory therapy.

Bacterial biofilm infections are intractable to traditional antibiotic treatment and usually cause persistent inflammation. Chemodynamic therapy (CDT) based on the Fenton reaction has recently emerged as a promising anti-biofilm strategy. However, the therapeutic efficacy of current Fenton agents often suffers from inefficient Fenton activity and lacks anti-inflammatory capability. Herein, FePS3 nanosheets (NSs) are explored for the first time as novel microenvironment-selective therapeutic nanoagents for bacterial biofilm infections with both self-enhanced Fenton activity for an anti-biofilm effect and reactive oxygen species (ROS) scavenging properties for an anti-inflammatory effect. In biofilms with acidic microenvironments, FePS3 NSs release Fe2+ to generate toxic ROS by Fenton reaction and reductive [P2S6]4- to enhance the Fenton activity by reducing Fe3+ to Fe2+. In the surrounding normal tissues with neutral pH, FePS3 NSs scavenge ROS by reductive [P2S6]4- with an anti-inflammatory effect. This work demonstrates multifunctional Fenton nanoagents with microenvironment-selective ROS generation and elimination properties for effective treatment of bacterial biofilm infections with both anti-biofilm and anti-inflammatory effects.

Biofilm Microenvironment-Responsive Nanotheranostics for Dual-Mode Imaging and Hypoxia-Relief-Enhanced Photodynamic Therapy of Bacterial Infections.

The formation of bacterial biofilms closely associates with infectious diseases. Until now, precise diagnosis and effective treatment of bacterial biofilm infections are still in great need. Herein, a novel multifunctional theranostic nanoplatform based on MnO2 nanosheets (MnO2 NSs) has been designed to achieve pH-responsive dual-mode imaging and hypoxia-relief-enhanced antimicrobial photodynamic therapy (aPDT) of bacterial biofilm infections. In this study, MnO2 NSs were modified with bovine serum albumin (BSA) and polyethylene glycol (PEG) and then loaded with chlorin e6 (Ce6) as photosensitizer to form MnO2-BSA/PEG-Ce6 nanosheets (MBP-Ce6 NSs). After being delivered into the bacterial biofilm-infected tissues, the MBP-Ce6 NSs could be decomposed in acidic biofilm microenvironment and release Ce6 with Mn2+, which subsequently activate both fluorescence (FL) and magnetic resonance (MR) signals for effective dual-mode FL/MR imaging of bacterial biofilm infections. Meanwhile, MnO2 could catalyze the decomposing of H2O2 in biofilm-infected tissues into O2 and relieve the hypoxic condition of biofilm, which significantly enhances the efficacy of aPDT. An in vitro study showed that MBP-Ce6 NSs could significantly reduce the number of methicillin-resistant Staphylococcus aureus (MRSA) in biofilms after 635 nm laser irradiation. Guided by FL/MR imaging, MRSA biofilm-infected mice can be efficiently treated by MBP-Ce6 NSs-based aPDT. Overall, MBP-Ce6 NSs not only possess biofilm microenvironment-responsive dual-mode FL/MR imaging ability but also have significantly enhanced aPDT efficacy by relieving the hypoxia habitat of biofilm, which provides a promising theranostic nanoplatform for bacterial biofilm infections.

Efficient Bacteria Killing by Cu2WS4 Nanocrystals with Enzyme-like Properties and Bacteria-Binding Ability.

Antibacterial agents with high antibacterial efficiency and bacteria-binding capability are highly desirable. Herein, we describe the successful preparation of Cu2WS4 nanocrystals (CWS NCs) with excellent antibacterial activity. CWS NCs with small size (∼20 nm) achieve more than 5 log (>99.999%) inactivation efficiency of both Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) at low concentration (<2 µg mL-1) with or without ambient light, which is much better than most of the reported antibacterial nanomaterials (including Ag, TiO2, etc.) and even better than the widely used antibiotics (vancomycin and daptomycin). Antibacterial mechanism study showed that CWS NCs have both enzyme-like (oxidase and peroxidase) properties and selective bacteria-binding ability, which greatly facilitate the production of reactive oxygen species to kill bacteria. Animal experiments further indicated that CWS NCs can effectively treat wounds infected with methicillin-resistant Staphylococcus aureus (MRSA). This work demonstrates that CWS NCs have the potential as effective antibacterial nanozymes for the treatment of bacterial infection.

Efficient biofunctionalization of MoS2 nanosheets with peptides as intracellular fluorescent biosensor for sensitive detection of caspase-3 activity.

Intracellular detection of caspase-3 activity is crucial for the study of cell apoptosis and caspase-3 related diseases. Although various nanomaterials-based biosensors have been constructed for this purpose, they often suffer from poor stability or complicated construction due to the lack of a facile and efficient biofunctionalization method, which decreases their sensing performance and limits their use in the complex physiological environments. As novel two-dimentional (2D) nanomaterials, MoS2 nanosheets (NSs) have shown great potential for biosensing due to their unique properties. Herein, we develop a versatile yet facile covalent biofucntionalization strategy of MoS2 NSs by utilizing polydopamine (PDA) as nano-bio interface, and construct an intracellular fluorescent biosensor (MoS2@PDA-PEG-Peptide, MPPP) for the determination of caspase-3 activity. This covalent biofunctionalization of MoS2 NSs can significantly improve the conjugation efficiency of biomolecules and enhance their stability in complicated environments, which is much better than conventional biofunctionalization by using thiol-metal coordination. Furthermore, this novel caspase-3 biosensor based on peptides biofunctionalized MoS2 NSs shows high sensitivity and selectivity for the detection of caspase-3 with a limit of detection (LOD) of 0.33 ng/mL, and can be used for high-contrast fluorescent imaging of cell apoptosis.