Quorum Sensing Interference Assisted Therapy-Based Magnetic Hyperthermia Amplifier for Synergistic Biofilm Treatment.

Biofilms offer bacteria a physical and metabolic barrier, enhancing their tolerance to external stress. Consequently, these biofilms limit the effectiveness of conventional antimicrobial treatment. Recently, quorum sensing (QS) has been linked to biofilm's stress response to thermal, oxidative, and osmotic stress. Herein, a multiple synergistic therapeutic strategy that couples quorum sensing interference assisted therapy (QSIAT)-mediated enhanced thermal therapy with bacteria-triggered immunomodulation in a single nanoplatform, is presented. First, as magnetic hyperthermia amplifier, hyaluronic acid-coated ferrite (HA@MnFe2 O4 ) attenuates the stress response of biofilm by down-regulating QS-related genes, including agrA, agrC, and hld. Next, the sensitized bacteria are eliminated with magnetic heat. QS interference and heat also destruct the biofilm, and provide channels for further penetration of nanoparticles. Moreover, triggered by bacterial hyaluronidase, the wrapped hyaluronic acid (HA) decomposes into disaccharides at the site of infection and exerts healing effect. Thus, by reversing the bacterial tissue invasion mechanism for antimicrobial purpose, tissue regeneration following pathogen invasion and thermal therapy is successfully attained. RNA-sequencing demonstrates the QS-mediated stress response impairment. In vitro and in vivo experiments reveal the excellent antibiofilm and anti-inflammatory effects of HA@MnFe2 O4 . Overall, QSIAT provides a universal enhancement strategy for amplifying the bactericidal effects of conventional therapy via stress response interference.

A natural killer cell mimic against intracellular pathogen infections.

In the competition between the pathogen infection and the host defense, infectious microorganisms may enter the host cells by evading host defense mechanisms and use the intracellular biomolecules as replication nutrient. Among them, intracellular Staphylococcus aureus relies on the host cells to protect itself from the attacks by antibiotics or immune system to achieve long-term colonization in the host, and the consequent clinical therapeutic failures and relapses after antibiotic treatment. Here, we demonstrate that intracellular S. aureus surviving well even in the presence of vancomycin can be effectively eliminated using an emerging cell-mimicking therapeutic strategy. These cell mimics with natural killer cell-like activity (NKMs) are composed of a redox-responsive degradable carrier, and perforin and granzyme B within the carrier. NKMs perform far more effectivly than clinical antibiotics in treating intracellular bacterial infections, providing a direct evidence of the NK cell-mimicking immune mechanism in the treatment of intracellular S. aureus.

Enhanced Bacterial Cuproptosis-Like Death via Reversal of Hypoxia Microenvironment for Biofilm Infection Treatment.

A recently emerging cell death pathway, known as copper-induced cell death, has demonstrated significant potential for treating infections. Existing research suggests that cells utilizing aerobic respiration, as opposed to those reliant on glycolysis, exhibit greater sensitivity to copper-induced death. Herein, a MnO2-loaded copper metal-organic frameworks platform is developed denoted as MCM, to enhance bacterial cuproptosis-like death via the remodeling of bacterial respiratory metabolism. The reversal of hypoxic microenvironments induced a cascade of responses, encompassing the reactivation of suppressed immune responses and the promotion of osteogenesis and angiogenesis. Initially, MCM catalyzed O2 production, alleviating hypoxia within the biofilm and inducing a transition in bacterial respiration mode from glycolysis to aerobic respiration. Subsequently, the sensitized bacteria, characterized by enhanced tricarboxylic acid cycle activity, underwent cuproptosis-like death owing to increased copper concentrations and aggregated intracellular dihydrolipoamide S-acetyltransferase (DLAT). The disruption of hypoxia also stimulated suppressed dendritic cells and macrophages, thereby strengthening their antimicrobial activity through chemotaxis and phagocytosis. Moreover, the nutritional effects of copper elements, coupled with hypoxia alleviation, synergistically facilitated the regeneration of bones and blood vessels. Overall, reshaping the infection microenvironment to enhance cuproptosis-like cell death presents a promising avenue for eradicating biofilms.

Effect of Fibular Allograft Augmentation in Medial Column Comminuted Proximal Humeral Fractures: A Randomized Controlled Trial.

BACKGROUND: Previous observational studies and meta-analyses have recommended augmentation with a fibular allograft (FA) during the treatment of proximal humeral fractures with locking plates (LPs). However, to our knowledge, randomized controlled trials comparing open reduction and internal fixation (ORIF) with and without FA have not been performed to date. METHODS: This was a randomized controlled trial in which adults with a medial column comminuted proximal humeral fracture were randomly allocated to undergo ORIF with an LP (the LP group) or with an LP augmented with an FA (the FA group). Patients were followed for 24 months. The primary outcome was the Disabilities of the Arm, Shoulder and Hand (DASH) score at 12 months after the surgical procedure. The secondary outcomes included the DASH score at other time points, shoulder function, pain score, satisfaction, complications, and changes in neck-shaft angle and humeral head height. RESULTS: From October 20, 2016, to December 24, 2019, 80 patients were randomized. There were 52 women (65%), and the mean patient age (and standard deviation) was 65 ± 14 years. Of the 80 patients, 39 were allocated to the FA group and 41 were allocated to the LP group. At the primary time point (12 months), the unadjusted mean between-group difference in DASH score was -1.2 (95% confidence interval [CI], -7.3 to 5.0; p = 0.71) favoring the FA group, and, with adjustment for smoking, alcohol drinking, and diabetes, the between-group difference was -1.4 (95% CI, -7.7 to 5.0; p = 0.67) favoring FA. No significant differences between the 2 groups were found among the secondary outcomes. CONCLUSIONS: No additional benefit was found for FA augmentation in treating medial column comminuted proximal humeral fractures. LEVEL OF EVIDENCE: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.

Erythrocyte membrane-enveloped molybdenum disulfide nanodots for biofilm elimination on implants via toxin neutralization and immune modulation.

Implant-related infections (IRIs) caused by bacterial biofilms remain a prevalent but tricky clinical issue, and are characterized by drug resistance, toxin impairment and immunosuppression. Recently, reactive oxygen species (ROS)- and hyperthermia-based antimicrobial therapies have been developed to effectively destroy biofilms. However, almost all of them have failed to simultaneously focus on the immunosuppressive biofilm microenvironment and bacterial toxin-induced tissue damage. Herein, we proposed a one-arrow-three-hawks strategy to orchestrate hyperthermia/ROS antibiofilm therapy, toxin neutralization and immunomodulatory therapy through engineering a bioinspired erythrocyte membrane-enveloped molybdenum disulfide nanodot (EM@MoS2) nanoplatform. In the biofilm microenvironment, pore-forming toxins actively attack the erythrocyte membranes on the nanodots and are detained, thus staying away from their targets and mitigating tissue damage. Under near-infrared (NIR) laser irradiation, MoS2 nanodots, with superb photothermal and peroxidase (POD)-like properties, exert a powerful synergistic antibiofilm effect. More intriguingly, we initially identified that they possessed the ability to reverse the immunosuppressive microenvironment by skewing the macrophages from an anti-inflammatory phenotype to a proinflammatory phenotype, which would promote the elimination of biofilm debris and prevent infection relapse. Systematic in vitro and in vivo evaluations have demonstrated that EM@MoS2 achieves a remarkable antibiofilm effect. The current study integrated the functions of hyperthermia/ROS therapy, virulence clearance and immune regulation, which could provide an effective paradigm for IRIs therapy.

Biomimetic Self-Assembling Metal-Organic Architectures with Non-Iridescent Structural Coloration for Synergetic Antibacterial and Osteogenic Activity of Implants.

Materials in nature feature versatile and programmable interactions to render macroscopic architectures with multiscale structural arrangements. By rationally combining metal-carboxylate and metal-organophosphate coordination interactions, Au25(MHA)18 (MHA, 6-mercaptohexanoic acid) nanocluster self-assembled structural color coating films and phytic acid (PA)-metal coordination complexes are sequentially constructed on the surface of titanium implants. The Lewis acid-base coordination principle applies for these metal-organic coordination networks. The isotropic arrangement of nanoclusters with a short-range order is investigated via grazing incidence wide-angle X-ray scattering. The integration of robust M-O (M = Ti, Zr, Hf) and labile Cu-O coordination bonds with high connectivity of Au25(MHA)18 nanoclusters enables these artificial photonic structures to achieve a combination of mechanical stability and bacteriostatic activity. Moreover, the colorless and transparent PA-metal complex layer allows the viewing of the structural color and surface wettability switching to hydrophilic and makes feasible the interfacial biomineralization of hydroxyapatite. Collectively, these modular metal-organic coordination-driven assemblies are predictive and rational material design strategies with tunable hierarchy and diversity. The complete metal-organic architectures will not only help improve the physicochemical properties of the bone-implant interface with synergistic antibacterial and osseointegration activities but also can boost surface engineering of medical metal implants.

Gold nanoclusters-loaded hydrogel formed by dimeric hydrogen bonds crosslinking: A novel strategy for multidrug-resistant bacteria-infected wound healing.

Restoring skin integrity after wound infection remains a tougher health challenge due to the uncontrolled antibiotic-resistant pathogens caused by antibiotic abuse. Herein, an injectable hydrogel with dual antibacterial and anti-inflammatory activities composed of gold nanoclusters (GNCs) and carbomer (CBM) is developed for wound dressing to overcome multidrug-resistant infection. Firstly, both experimental investigations and molecular dynamics simulation validate the protonation state of 6-mercaptohexanoic acid (MHA) ligands play an important role in its antibacterial action of GNCs. The self-organizing GNCs-CBM composite hydrogel is then spontaneously cross-linked by the dimeric hydrogen bonds (H-bonds) between the MHA ligands and the acrylic acid groups of CBM. Benefitting from the dimeric H-bonds, the hydrogel becomes thickening enough as an ideal wound dressing and the GNCs exist in the hydrogel with a high protonation level that contributes to the enhanced bactericidal function. In all, by combining bactericidal and immunomodulatory actions, the GNCs-CBM hydrogel demonstrated excellent synergy in accelerating wound healing in animal infection models. Hence, the dimeric H-bonds strengthening strategy makes the GNCs-CBM hydrogel hold great potential as a safe and effective dressing for treating infected wounds.

2D Janus carrier-enabled trojan horse: Gallium delivery for the sequential therapy of biofilm associated infection.

Biofilm-associated infections (BAIs) continue to pose a major challenge in the medical field. Nanomedicine, in particular, promises significant advances in combating BAIs through the introduction of a variety of nanomaterials and nano-antimicrobial strategies. However, studies to date have primarily focused on the removal of the bacterial biofilm and neglect the subsequent post-biofilm therapeutic measures for BAIs, rendering pure anti-biofilm strategies insufficient for the holistic recovery of affected patients. Herein, we construct an emerging dual-functional composite nanosheet (SiHx@Ga) that responds to pHs fluctuation in the biofilm microenvironment to enable a sequential therapy of BAIs. In the acidic environment of biofilm, SiHx@Ga employs the self-sensitized photothermal Trojan horse strategy to effectively impair the reactive oxygen species (ROS) defense system while triggering oxidative stress and lipid peroxidation of bacteria, engendering potent antibacterial and anti-biofilm effects. Surprisingly, in the post-treatment phase, SiHx@Ga adsorbs free pathogenic nucleic acids released after biofilm destruction, generates hydrogen with ROS-scavenging and promotes macrophage polarization to the M2 type, effectively mitigating damaging inflammatory burst and promoting tissue healing. This well-orchestrated strategy provides a sequential therapy of BAIs by utilizing microenvironmental variations, offering a conceptual paradigm shift in the field of nanomedicine anti-infectives.