Neutrophil-inspired photothermo-responsive drug delivery system for targeted treatment of bacterial infection and endotoxins neutralization.

BACKGROUND: P. aeruginosa, a highly virulent Gram-negative bacterium, can cause severe nosocomial infections, and it has developed resistance against most antibiotics. New therapeutic strategies are urgently needed to treat such bacterial infection and reduce its toxicity caused by endotoxin (lipopolysaccharide, LPS). Neutrophils have been proven to be able to target inflammation site and neutrophil membrane receptors such as Toll-like receptor-4 (TLR4) and CD14, and exhibit specific affinity to LPS. However, antibacterial delivery system based on the unique properties of neutrophils has not been reported. METHODS: A neutrophil-inspired antibacterial delivery system for targeted photothermal treatment, stimuli-responsive antibiotic release and endotoxin neutralization is reported in this study. Specifically, the photothermal reagent indocyanine green (ICG) and antibiotic rifampicin (RIF) are co-loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP-ICG/RIF), followed by coating with neutrophil membrane to obtain antibacterial delivery system (NM-NP-ICG/RIF). The inflammation targeting properties, synergistic antibacterial activity of photothermal therapy and antibiotic treatment, and endotoxin neutralization have been studied in vitro. A P. aeruginosa-induced murine skin abscess infection model has been used to evaluate the therapeutic efficacy of the NM-NP-ICG/RIF. RESULTS: Once irradiated by near-infrared lasers, the heat generated by NP-ICG/RIF triggers the release of RIF and ICG, resulting in a synergistic chemo-photothermal antibacterial effect against P. aeruginosa (~ 99.99% killing efficiency in 5 min). After coating with neutrophil-like cell membrane vesicles (NMVs), the nanoparticles (NM-NP-ICG/RIF) specifically bind to inflammatory vascular endothelial cells in infectious site, endowing the nanoparticles with an infection microenvironment targeting function to enhance retention time. Importantly, it is discovered for the first time that NMVs-coated nanoparticles are able to neutralize endotoxins. The P. aeruginosa murine skin abscess infection model further demonstrates the in vivo therapeutic efficacy of NM-NP-ICG/RIF. CONCLUSION: The neutrophil-inspired antibacterial delivery system (NM-NP-ICG/RIF) is capable of targeting infection microenvironment, neutralizing endotoxin, and eradicating bacteria through a synergistic effect of photothermal therapy and antibiotic treatment. This drug delivery system made from FDA-approved compounds provides a promising approach to fighting against hard-to-treat bacterial infections.

Ultralow Charge Voltage Triggering Exceptional Post-Charging Antibacterial Capability of Co3 O4 /MnOOH Nanoneedles for Skin Infection Treatment.

The post-charging antibacterial therapy is highly promising for treatment of Gram-negative bacterial wound infections. However, the therapeutic efficacy of the current electrode materials is yet unsatisfactory due to their low charge storage capacity and limited reactive oxygen species (ROS) yields. Herein, the design of MnOOH decorated Co3 O4 nanoneedles (MCO) with exceptional post-charging antibacterial effect against Gram-negative bacteria at a low charge voltage and their implementation as a robust antibacterial electrode for skin wound treatment are reported. Taking advantaging of the increased active sites and enhanced OH- adsorption capability, the charge storage capacity and ROS production of the MCO electrode are remarkably boosted. As a result, the MCO electrode after charging at an ultralow voltage of 1.4 V gives a 5.49 log and 5.82 log bacterial reduction in Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) within an incubation time of only 5 min, respectively. More importantly, the antibacterial efficiency of the MCO electrode against multi-drug resistant (MDR) bacteria including Klebsiella pneumoniae (K. pneumoniae) and Acinetobacter baumannii (A. baumannii) also reaches 99.999%. In addition, the MCO electrode exhibits excellent reusability, and the role of extracellular ROS in enhancing post-charging antibacterial activity is also unraveled.

Selective Capture, Separation, and Photothermal Inactivation of Methicillin-Resistant Staphylococcus aureus (MRSA) Using Functional Magnetic Nanoparticles.

Antibiotic-free antimicrobial strategies are urgently needed to address the rapid evolution of antimicrobial resistance and transmission of multidrug-resistance bacterial infections. Herein, we fabricated polydopamine-coated porous magnetic nanoparticles (pMNPs@PDA) for effective separation and photothermal killing of methicillin-resistant Staphylococcus aureus (MRSA). Taking advantage of the excellent bacteria-affinitive property of polydopamine, the nanoparticles were anchored on the surface of bacteria, permitting rapid and efficient MRSA capture and separation with over 99% removal via the application of a magnetic field in 30 min. It was found, for the first time, that polydopamine-coated magnetic nanoparticles displayed a selective capture of Gram-positive bacteria when compared with Gram-negative bacteria. The selectivity was attributed to the preferable binding capability of pMNPs@PDA to peptidoglycan (PGN) of Gram-positive bacteria, compared to the lipopolysaccharide (LPS) of Gram-negative bacteria. With the magnetic separation and photothermal properties, pMNPs@PDA exhibited efficient killing of the captured MRSA under the irradiation of near-infrared (NIR) light. Cell cytotoxicity testing demonstrated good biocompatibility of the nanoparticles. These antibiotic-free nanoparticles capable of fast capture, separation, and inactivation of MRSA may be potentially used for water disinfection, blood purification, and treatment of bacterial infections.

Repurposing Non-Antibiotic Drugs Auranofin and Pentamidine in Combination to Combat Multidrug-Resistant Gram-Negative Bacteria.

OBJECTIVES: Infections caused by multidrug-resistant (MDR) bacteria, especially MDR Gram-negative bacteria, have posed a great challenge to healthcare systems globally. To address the shortage of effective antibiotics against MDR Gram-negative bacterial infections, two non-antibiotic drugs - auranofin (rheumatoid arthritis drug) and pentamidine (antiprotozoal drug) - are being repurposed to treat MDR Gram-negative bacteria by a combination approach. METHODS: Chequerboard microdilution assay was used to determine the interaction of auranofin and pentamidine against drug-susceptible and MDR Gram-negative bacteria (Escherichia coli, Acinetobacter baumannii and Klebsiella pneumoniae). Fluorescence microscopy, scanning electron microscopy and inductively coupled plasma mass spectrometry were used to explore the mechanism of synergistic antibacterial effect. RESULTS: These two non-antibiotic drugs displayed a strong synergistic antibacterial effect, with the fraction inhibitory concentration index ranging 0.094-0.506. The MIC of auranofin reduced by as much as ≥ 1024-fold when combined with pentamidine at sub-MIC. Fluorescence and inductively coupled plasma mass spectrometry analyses revealed that bacterial membrane disruption caused by pentamidine treatment at sub-MIC led to an increased intracellular auranofin content with the combination treatment. The enhanced auranofin uptake in bacteria resulted in efficient bacterial killing. More importantly, the auranofin/pentamidine combination slowed down auranofin resistance development in clinically isolated MDR bacteria (Klebsiella pneumoniae) more than the combination of auranofin and colistin, which is a last-line antibiotic with a membrane-lytic antibacterial mechanism. CONCLUSION: The combination of non-antibiotic drugs with complementary antibacterial mechanisms provides a potentially promising approach to discover new antibacterial drugs and delay drug resistance development.

Co3 O4 Nanowires Capable of Discharging Low Voltage Electricity Showing Potent Antibacterial Activity for Treatment of Bacterial Skin Infection.

Overuse of antibiotics has led to multidrug resistance in bacteria, posing a tremendous challenge to the healthcare system. There is an urgent need to explore unconventional strategies to overcome this issue. Herein, for the first time, we report a capacitive Co3 O4 nanowire (NW) electrode coated on flexible carbon cloth, which is capable of eliminating bacteria while discharging, for the treatment of skin infection. Benefiting from the unique NW-like morphology, the Co3 O4 NW electrode with increased active sites and enhanced capacitive property exhibits a prominent antibacterial effect against both Gram-positive and Gram-negative bacteria after charging at a low voltage of 2 V for 30 min. Furthermore, the electrode is demonstrated to be recharged for multiple antibacterial treatment cycles without significant change of antibacterial activity, allowing for practical use in a non-clinical setting. More importantly, this Co3 O4 NW electrode is capable of damaging bacterial cell membrane and inducing the accumulation of intracellular reactive oxygen species without impairing viability of skin keratinocytes. In a mouse model of bacterial skin infection, the Co3 O4 electrode shows significant therapeutic efficacy by eradicating colonized bacteria, thus accelerating the healing process of infected wounds. This nanostructured capacitive electrode provides an antibiotic-free, rechargeable, and wearable approach to treat bacterial skin infection.

Synthetic peptide hydrogels as 3D scaffolds for tissue engineering.

The regeneration of tissues and organs poses an immense challenge due to the extreme complexity in the research work involved. Despite the tissue engineering approach being considered as a promising strategy for more than two decades, a key issue impeding its progress is the lack of ideal scaffold materials. Nature-inspired synthetic peptide hydrogels are inherently biocompatible, and its high resemblance to extracellular matrix makes peptide hydrogels suitable 3D scaffold materials. This review covers the important aspects of peptide hydrogels as 3D scaffolds, including mechanical properties, biodegradability and bioactivity, and the current approaches in creating matrices with optimized features. Many of these scaffolds contain peptide sequences that are widely reported for tissue repair and regeneration and these peptide sequences will also be discussed. Furthermore, 3D biofabrication strategies of synthetic peptide hydrogels and the recent advances of peptide hydrogels in tissue engineering will also be described to reflect the current trend in the field. In the final section, we will present the future outlook in the design and development of peptide-based hydrogels for translational tissue engineering applications.