Hybrid Cell Membrane-Based Nanoplatforms for Enhanced Immunotherapy against Cancer and Infectious Diseases.

Immunotherapy based on nanoplatforms is a promising approach to treat cancer and infectious diseases, and it has achieved considerable progress in clinical practices. Cell membrane-based nanoplatforms endow nanoparticles with versatile characteristics, such as half-life extension, targeting ability, and immune-system regulation. However, monotypic cell membrane usually fails to provoke strong immune response for immunotherapy while maintaining good biosafety. The integration of different cell-membrane types provides a promising approach to construct multifunctional nanoplatforms for improved immunotherapeutic efficacy by enhancing immunogenicity or targeting function, evading immune clearance, or combining with other therapeutic modalities. In this review, the design principles, preparation strategies, and applications of hybrid cell membrane-based nanoplatforms for cancer and infection immunotherapy are first discussed. Furthermore, the challenges and prospects for the potential clinical translation of hybrid cell membrane-based nanoplatforms are discussed.

Polymeric micellar nanoparticles for effective CRISPR/Cas9 genome editing in cancer.

The clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) gene editing has attracted extensive attentions in various fields, however, its clinical application is hindered by the lack of effective and safe delivery system. Herein, we reported a cationic micelle nanoparticle composed of cholesterol-modified branched small molecular PEI (PEI-CHO) and biodegradable PEG-b-polycarbonate block copolymer (PEG-PC), denoted as PEG-PC/PEI-CHO/pCas9, for the CRISPR/Cas9 delivery to realize genomic editing in cancer. Specifically, PEI-CHO condensed pCas9 into nanocomplexes, which were further encapsulated into PEG-PC nanoparticles (PEG-PC/PEI-CHO/pCas9). PEG-PC/PEI-CHO/pCas9 had a PEG shell, protecting DNA from degradation by nucleases. Enhanced cellular uptake of PEG-PC/PEI-CHO/pCas9 nanoparticles was observed as compared to that mediated by Lipo2k/pCas9 nanoparticles, thus leading to significantly elevated transfection efficiency after escaping from endosomes via the proton sponge effect of PEI. In addition, the presence of PEG shell greatly improved biocompatibility, and significantly enhanced the in vivo tumor retention of pCas9 compared to PEI-CHO/pCas9. Notably, apparent downregulation of GFP expression could be achieved both in vitro and in vivo by using PEG-PC/PEI-CHO/pCas9-sgGFP nanoparticles. Furthermore, PEG-PC/PEI-CHO/pCas9-sgMcl1 induced effective apoptosis and tumor suppression in a HeLa tumor xenograft mouse model by downregulating Mcl1 expression. This work may provide an alternative paradigm for the efficient and safe genome editing in cancer.

Biofunctional lipid nanoparticles for precision treatment and prophylaxis of bacterial infections.

The lack of bacterial-targeting function in antibiotics and their prophylactic usage have caused overuse of antibiotics, which lead to antibiotic resistance and inevitable long-term toxicity. To overcome these issues, we develop neutrophil-bacterial hybrid cell membrane vesicle (HMV)-coated biofunctional lipid nanoparticles (LNP@HMVs), which are designed to transport antibiotics specifically to bacterial cells at the infection site for the effective treatment and prophylaxis of bacterial infection. The dual targeting ability of HMVs to inflammatory vascular endothelial cells and homologous Gram-negative bacterial cells results in targeted accumulation of LNP@HMVs in the site of infections. LNP@HMVs loaded with the antibiotic norfloxacin not only exhibit enhanced activity against planktonic bacteria and bacterial biofilms in vitro but also achieve potent therapeutic efficacy in treating both systemic infection and lung infection. Furthermore, LNP@HMVs trigger the activation of specific humoral and cellular immunity to prevent bacterial infection. Together, LNP@HMVs provide a promising strategy to effectively treat and prevent bacterial infection.

Age-related bone diseases: Role of inflammaging.

Bone aging is characterized by an imbalance in the physiological and pathological processes of osteogenesis, osteoclastogenesis, adipogenesis, and chondrogenesis, resulting in exacerbated bone loss and the development of age-related bone diseases, including osteoporosis, osteoarthritis, rheumatoid arthritis, and periodontitis. Inflammaging, a novel concept in the field of aging research, pertains to the persistent and gradual escalation of pro-inflammatory reactions during the aging process. This phenomenon is distinguished by its low intensity, systemic nature, absence of symptoms, and potential for management. The mechanisms by which inflammaging contribute to age-related chronic diseases, particularly in the context of age-related bone diseases, remain unclear. The precise manner in which systemic inflammation induces bone aging and consequently contributes to the development of age-related bone diseases has yet to be fully elucidated. This article primarily examines the mechanisms underlying inflammaging and its association with age-related bone diseases, to elucidate the potential mechanisms of inflammaging in age-related bone diseases and offer insights for developing preventive and therapeutic strategies for such conditions.

The influence and therapeutic effect of microbiota in systemic lupus erythematosus.

Systemic erythematosus lupus (SLE) is an autoimmune disease involving multiple organs that poses a serious risk to the health and life of patients. A growing number of studies have shown that commensals from different parts of the body and exogenous pathogens are involved in SLE progression, causing barrier disruption and immune dysregulation through multiple mechanisms. However, they sometimes alleviate the symptoms of SLE. Many factors, such as genetic susceptibility, metabolism, impaired barriers, food, and sex hormones, are involved in SLE, and the microbiota drives the development of SLE either by depending on or interacting with these factors. Among these, the crosstalk between genetic susceptibility, metabolism, and microbiota is a hot topic of research and is expected to lay the groundwork for the amelioration of the mechanism, diagnosis, and treatment of SLE. Furthermore, the microbiota has great potential for the treatment of SLE. Ideally, personalised therapeutic approaches should be developed in combination with more specific diagnostic methods. Herein, we provide a comprehensive overview of the role and mechanism of microbiota in lupus of the intestine, oral cavity, skin, and kidney, as well as the therapeutic potential of the microbiota.

PMVT: a lightweight vision transformer for plant disease identification on mobile devices.

Due to the constraints of agricultural computing resources and the diversity of plant diseases, it is challenging to achieve the desired accuracy rate while keeping the network lightweight. In this paper, we proposed a computationally efficient deep learning architecture based on the mobile vision transformer (MobileViT) for real-time detection of plant diseases, which we called plant-based MobileViT (PMVT). Our proposed model was designed to be highly accurate and low-cost, making it suitable for deployment on mobile devices with limited resources. Specifically, we replaced the convolution block in MobileViT with an inverted residual structure that employs a 7×7 convolution kernel to effectively model long-distance dependencies between different leaves in plant disease images. Furthermore, inspired by the concept of multi-level attention in computer vision tasks, we integrated a convolutional block attention module (CBAM) into the standard ViT encoder. This integration allows the network to effectively avoid irrelevant information and focus on essential features. The PMVT network achieves reduced parameter counts compared to alternative networks on various mobile devices while maintaining high accuracy across different vision tasks. Extensive experiments on multiple agricultural datasets, including wheat, coffee, and rice, demonstrate that the proposed method outperforms the current best lightweight and heavyweight models. On the wheat dataset, PMVT achieves the highest accuracy of 93.6% using approximately 0.98 million (M) parameters. This accuracy is 1.6% higher than that of MobileNetV3. Under the same parameters, PMVT achieved an accuracy of 85.4% on the coffee dataset, surpassing SqueezeNet by 2.3%. Furthermore, out method achieved an accuracy of 93.1% on the rice dataset, surpassing MobileNetV3 by 3.4%. Additionally, we developed a plant disease diagnosis app and successfully used the trained PMVT model to identify plant disease in different scenarios.

Antibiotic-Polymer Self-Assembled Nanocomplex to Reverse Phenotypic Resistance of Bacteria toward Last-Resort Antibiotic Colistin.

Colistin is the last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections that are untreatable by other clinically available antibiotics. However, the recently merged plasmid-borne gene mobilized colistin resistance (mcr) leads to modification of the colistin target (i.e., bacterial membrane), greatly compromising the therapy outcome of colistin. To address this unmet clinical need, a nanocomplex (CMS-pEt_20 NP) of anionic prodrug colistin methanesulfonate (CMS) and guanidinium-functionalized cationic polymer pEt_20 is developed through facile self-assembly for co-delivering an antibiotic and antimicrobial polymer with membrane affinity to reverse colistin resistance. The CMS-pEt_20 NP formation enables reversal of colistin resistance and complete killing of clinically isolated mcr-positive colistin-resistant bacteria including MDR E. coli and K. pneumoniae, while monotreatment of polymer or antibiotic at equivalent doses exhibits no antibacterial activity. Mechanistic studies reveal that the CMS-pEt_20 NP enhanced the affinity of delivered CMS to the modified membrane of colistin-resistant bacteria, reviving the membrane lytic property of colistin. The increased membrane permeability caused by colistin in turn promotes an influx of pEt_20 to generate intracellular ROS stress, resulting in elimination of colistin-resistant bacteria. More importantly, a colistin-resistant mouse peritonitis-sepsis infection model demonstrates the excellent therapeutic efficacy of CMS-pEt_20 NP with 100% survival of the infected mouse. In addition, the nanocomplex is proven not toxic both in vitro and in vivo. Taken together, the self-assembled antibiotic-polymer nanocomplex with two complementary antibacterial mechanisms successfully reverses the colistin resistance phenotype in bacteria, and it can be a potential strategy to treat untreatable colistin-resistant MDR bacterial infections.

Liposomes Co-Delivering Curcumin and Colistin to Overcome Colistin Resistance in Bacterial Infections.

Antibiotic colistin is the last line of defense against multidrug-resistant (MDR) Gram-negative bacterial infections. Emergence of colistin resistance in microbes is a critical challenge. Herein, curcumin is discovered, for the first time, to reverse the resistance phenotype of colistin-resistant bacteria via a checkerboard assay. For the co-delivery of curcumin and colistin, negatively charged poly(ethylene glycol)-functionalized liposomes encapsulating both drugs (Lipo-cc) are prepared. Killing kinetics and live/dead assays confirm the antibacterial activity of Lipo-cc against colistin-resistant bacteria, which is more potent than that of the free curcumin and colistin combination. Mechanistical studies reveal that Lipo-cc restores the affinity of colistin for the bacterial membrane and improves the uptake of curcumin, which leads to reduced efflux pump activity, achieving a synergistic effect of colistin and curcumin. At the effective antibacterial dose, Lipo-cc does not exhibit any toxicity. The therapeutic efficacy of Lipo-cc is further demonstrated in an intestinal bacterial infection model induced with colistin-resistant Escherichia coli. Lipo-cc reduces the bacterial burden with over 6-log reduction and alleviated inflammation caused by infection. Importantly, unlike colistin, Lipo-cc does not affect the homeostasis of the intestinal flora. Taken together, Lipo-cc successfully overcame colistin resistance, indicating its potential for the treatment of colistin-resistant bacterial infections.

Cell-active, irreversible covalent inhibitors that selectively target the catalytic lysine of EGFR by using fluorosulfate-based SuFEx chemistry.

EGFR signaling is involved in multiple cellular processes including cell proliferation, differentiation and development, making this protein kinase one of the most valuable drug targets for the treatment of non-small cell lung carcinomas (NSCLC). Herein, we describe the design and synthesis of a series of potential covalent inhibitors targeting the catalytically conserved lysine (K745) of EGFR on the basis of Erlotinib, an FDA-approved first-generation EGFR drug. Different amine-reactive electrophiles were introduced at positions on the Erlotinib scaffold proximal to K745 in EGFR. The optimized compound 26 (as well as its close analog 30), possessing a novel arylfluorosulfate group (ArOSO2F), showed excellent in vitro potency (as low as 0.19 nM in independent IC50 determination) and selectivity against EGFR and many of its drug-resistant mutants. Both intact protein mass spectrometry (MS) and site-mapping analysis revealed that compound 26 covalently bound to EGFR at K745 through the formation of a sulfamate. In addition, compound 26 displayed good anti-proliferative potency against EGFR-overexpressing HCC827 cells by inhibiting endogenous EGFR autophosphorylation. The pharmacokinetic studies of compound 26 demonstrated the druggable potential of other ArOSO2F-containing compounds. Finally, competitive activity-based protein profiling (ABPP), cellular thermal shift assay (CETSA), as well as cellular wash-out experiments, all showed compound 26 to be the first cell-active, fluorosulfate-based targeted covalent inhibitor (TCI) of protein kinases capable of covalently engaging the catalytically conserved lysine of its target in live mammalian cells.

Encapsulation of Nano-Bortezomib in Apoptotic Stem Cell-Derived Vesicles for the Treatment of Multiple Myeloma.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.

Gastric Acid-Responsive ROS Nanogenerators for Effective Treatment of Helicobacter pylori Infection without Disrupting Homeostasis of Intestinal Flora.

Helicobacter pylori (H. pylori) has infected more than half of the world's population, and is the major cause of gastric cancer. The efficacy of standard antibiotic-based triple therapy is declining due to drug resistance development. Herein, a pH-responsive reactive oxygen species (ROS) nanogenerator (Fe-HMME@DHA@MPN) composed of acid-responsive metal polyphenol network (MPN) shell and mesoporous metal-organic nanostructure core [Fe-HMME (hematoporphyrin monomethyl ether, sonosensitizer)] loaded with dihydroartemisinin (DHA) is reported. These nanoparticles generate more ROS singlet oxygen than sonosensitizer HMME under ultrasonication, and this sonodynamic process is fueled by oxygen generated through Fenton/Fenton-like reactions of the degraded product in gastric acid Fe (II) and hydrogen peroxide (H2 O2 ) in the infection microenvironment. The encapsulated DHA, as a hydroperoxide source, is found to enhance the peroxidase-like activity of the Fe-HMME@DHA@MPN to generate ROS hydroxyl radical, beneficial for the microenvironment without sufficient H2 O2 . In vitro experiments demonstrate that the ROS nanogenerators are capable of killing multidrug-resistant H. pylori and removing biofilm, and ROS nanogenerators show high therapeutic efficacy in a H. pylori infection mouse model. Unlike the triple therapy, the nanogenerators display negligible side effects toward the normal gut microbiota. Taken together, these self-enhanced ROS nanogenerators have a great potential for treatment of H. pylori infection.

Immunotoxicity of metal and metal oxide nanoparticles: from toxic mechanisms to metabolism and outcomes.

The influence of metal and metal oxide nanomaterials on various fields since their discovery has been remarkable. They have unique properties, and therefore, have been employed in specific applications, including biomedicine. However, their potential health risks cannot be ignored. Several studies have shown that exposure to metal and metal oxide nanoparticles can lead to immunotoxicity. Different types of metals and metal oxide nanoparticles may have a negative impact on the immune system through various mechanisms, such as inflammation, oxidative stress, autophagy, and apoptosis. As an essential factor in determining the function and fate of immune cells, immunometabolism may also be an essential target for these nanoparticles to exert immunotoxic effects in vivo. In addition, the biodegradation and metabolic outcomes of metal and metal oxide nanoparticles are also important considerations in assessing their immunotoxic effects. Herein, we focus on the cellular mechanism of the immunotoxic effects and toxic effects of different types of metal and metal oxide nanoparticles, as well as the metabolism and outcomes of these nanoparticles in vivo. Also, we discuss the relationship between the possible regulatory effect of nanoparticles on immunometabolism and their immunotoxic effects. Finally, we present perspectives on the future research and development direction of metal and metal oxide nanomaterials to promote scientific research on the health risks of nanomaterials and reduce their adverse effects on human health.

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.

Interpenetrating Polymer Network Hydrogels Formed Using Antibiotics as a Dynamic Crosslinker for Treatment of Infected Wounds.

Antibacterial hydrogels, particularly antibiotic-loaded hydrogels, are promising wound dressing materials for treatment of bacteria-infected wound. However, it is challenging to achieve sustained release of antibiotics from hydrogels through physical encapsulation of the antibiotics. Herein, an interpenetrating polymer network P(AA-co-HEMA)Gen hydrogel is reported with double crosslinking formed by free radical polymerization of 2-hydroxyethyl methacrylate (HEMA) and acrylic acid (AA), while using the antibiotic gentamicin (Gen) as the dynamic physical crosslinker. Gentamicin is incorporated into the hydrogel networks via electrostatic interaction between the carboxyl groups of poly(acrylic acid) and the amino groups of gentamicin, which leads to pH-responsive drug release and a significant increase in mechanical strength (i.e., elastic modulus, viscous modulus, and compressive modulus). More importantly, the hydrogels with optimal compositions demonstrate long-lasting antibacterial activity against both Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli) over 28 d. The in vivo studies that are conducted in an S. aureus-infected full-thickness skin wound model demonstrate that the double crosslinking hydrogels loaded with gentamicin eliminate bacteria in the wounds more effectively and significantly accelerate wound healing as compared to 3M dressing and the control without any treatment. Taken together, this antibiotic-loaded interpenetrating polymer network hydrogel is potentially a promising wound dressing material for the treatment of bacteria-infected wound.

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.

Intracellular Co-delivery of native antibody and siRNA for combination therapy by using biodegradable silica nanocapsules.

Combination therapy is a promising strategy for treating multidrug-resistant (MDR) cancers. Macromolecules such as antibodies and RNAs have been successfully used for targeted therapy owing to their high specificity. However, their application as therapeutics remains limited due to membrane impermeability and poor intracellular stability. Designing drug delivery systems capable of co-administering macromolecules is therefore crucial for advancing them as therapeutics for combination therapy. Herein, by using glutathione (GSH)-responsive biodegradable silica nanocapsules (BS-NPs), we report for the first time a highly versatile nanomaterial-based strategy for co-encapsulation and intracellular co-delivery of different combinations of macromolecules (i.e., siRNA/protein, siRNA/antibody and protein/antibody). This strategy was successfully used in the intracellular co-delivery of siRNA/Cetuximab (also named Erbitux™) for combination therapy in epidermal growth factor receptor (EGFR)-overexpressing cancer cells. These BS-NPs showed good biosafety profiles and antitumor efficacy when administered in vivo, suggesting that the strategy holds potential as a novel delivery platform for combination cancer therapy.

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.