Harnessing the Potential of a Nitroreductase-Responsive Fluorescent Probe for the Diagnosis of Bacterial Keratitis.

Bacterial keratitis, an ocular emergency, is the predominant cause of infectious keratitis. However, diagnostic procedures for it are invasive, time-consuming, and expeditious, thereby limiting effective treatment for the disease in the clinic. It is imperative to develop a timely and convenient method for the noninvasive diagnosis of bacterial keratitis. Fluorescence imaging is a convenient and noninvasive diagnostic method with high sensitivity. In this study, a type of nitroreductase-responsive probe (NTRP), which responds to nitroreductase to generate fluorescence signals, was developed as an activatable fluorescent probe for the imaging diagnosis of bacterial keratitis. Imaging experiments both in vitro and in vivo demonstrated that the probe exhibited "turn-on" fluorescence signals in response to nitroreductase-secreting bacteria within 10 min. Furthermore, the fluorescence intensity reached its highest at 4 or 6 h in vitro and at 30 min in vivo when the excitation wavelength was set at 520 nm. Therefore, the NTRP has the potential to serve as a feasible agent for the rapid and noninvasive in situ fluorescence diagnosis of bacterial keratitis.

Zinc Doping Engineering in ZnxFe3-xO4 Heterostructures for Enhancing Photodynamic Therapy in the Near-Infrared-II Region.

Currently, photodynamic therapy (PDT) is restricted by the laser penetration depth. Except for PDT at 1064 nm wavelength excitation, the development of other NIR-II-activated nanomaterials with a higher response depth is still hindered and rarely reported in the literature. To overcome these problems, we fabricated a nanoplatform with heterostructures that generate reactive oxygen species (ROS) and ferrite nanoparticles under a high concentration of zinc doping (ZnxFe3-xO4 NPs), which can achieve oxidative damage of tumor cells under near-infrared (NIR) illumination. The recombination of photoelectrons and holes has been markedly inhibited due to the formation of heterostructures in the interfaces, thus greatly enhancing the capability for ROS and oxygen production by modulating the single-component doping content. The efficiency of PDT was verified by in vivo and in vitro assays under NIR light. Our results revealed that NIR-II (1208 nm) light irradiation of ZnxFe3-xO4 NPs exerted a remarkable antitumor activity, superior to NIR-I light (808 nm). More importantly, the reported ZnxFe3-xO4 NPs strategy provides an opportunity for the success of comparison with light in the first and second near-infrared regions.

VISTA antibody-loaded Fe3O4@TiO2 nanoparticles for sonodynamic therapy-synergistic immune checkpoint therapy of pancreatic cancer.

Breaking the poor permeability of immune checkpoint inhibitors (ICIs) caused by the stromal barrier and reversing the immunosuppressive microenvironment are significant challenges in pancreatic cancer immunotherapy. In this study, we synthesized core-shell Fe3O4@TiO2 nanoparticles to act as carriers for loading VISTA monoclonal antibodies to form Fe3O4@TiO2@VISTAmAb (FTV). The nanoparticles are designed to target the overexpressed ICIs VISTA in pancreatic cancer, aiming to improve magnetic resonance imaging-guided sonodynamic therapy (SDT)-facilitated immunotherapy. Laser confocal microscopy and flow cytometry results demonstrate that FTV nanoparticles are specifically recognized and phagocytosed by Panc-2 cells. In vivo experiments reveal that ultrasound-triggered TiO2 SDT can induce tumor immunogenic cell death (ICD) and recruit T-cell infiltration within the tumor microenvironment by releasing damage-associated molecular patterns (DAMPs). Furthermore, ultrasound loosens the dense fibrous stroma surrounding the pancreatic tumor and increases vascular density, facilitating immune therapeutic efficiency. In summary, our study demonstrates that FTV nanoparticles hold great promise for synergistic SDT and immunotherapy in pancreatic cancer.

Mild phototherapy mediated by IR780-Gd-OPN nanomicelles suppresses atherosclerotic plaque progression through the activation of the HSP27-regulated NF-κB pathway.

Reducing plaque lipid content and enhancing plaque stability without causing extensive apoptosis of foam cells are ideal requirements for developing a safe and effective treatment of atherosclerosis. In this study, we synthesized IR780-Gd-OPN nanomicelles by conjugating osteopontin (OPN) and loading a gadolinium-macrocyclic ligand (Gd-DOTA) onto near-infrared dye IR780-polyethylene glycol polymer. The nanomicelles were employed for mild phototherapy of atherosclerotic plaques and dual-mode imaging with near-infrared fluorescence and magnetic resonance. In vitro results reveal that the mild phototherapy mediated by IR780-Gd-OPN nanomicelles not only activates heat shock protein (HSP) 27 to protect foam cells against apoptosis but also inhibits the nuclear factor kappa-B (NF-κB) pathway to regulate lipid metabolism and macrophage polarization, thereby diminishing the inflammatory response. In vivo results further validate that mild phototherapy effectively reduces plaque lipid content and size while simultaneously enhancing plaque stability by regulating the ratio of M1 and M2-type macrophages. In summary, this study presents a promising approach for developing a safe and highly efficient method for the precise therapeutic visualization of atherosclerosis. STATEMENT OF SIGNIFICANCE: The rupture of unstable atherosclerotic plaques is a major cause of high mortality rates in cardiovascular diseases. Therefore, the ideal outcome of atherosclerosis treatment is to reduce plaque size while enhancing plaque stability. To address this challenge, we designed IR780-Gd-OPN nanomicelles for mild phototherapy of atherosclerosis. This treatment can effectively reduce plaque size while significantly improving plaque stability by increasing collagen fiber content and elevating the ratio of M2/M1 macrophages, which is mainly attributed to the inhibition of the NF-κB signaling pathway by mild phototherapy-activated HSP27. In summary, our proposed mild phototherapy strategy provides a promising approach for safe and effective treatment of atherosclerosis.

Ebola Virus Disease Outbreaks: Lessons Learned From Past and Facing Future Challenges.

INTRODUCTION: The purpose of this review is to examine African Ebola outbreaks from their first discovery to the present, to determine how the medical and public health response has changed and identify the causes for those changes. We sought to describe what is now known about the epidemiology and spread of Ebola virus disease (EVD) from the significant outbreaks that have occurred and outbreak control methods applied under often challenging circumstances. Given the substantial role that the U.S. Government and the U.S. DoD have played in the 2014 to 2016 West African Ebola outbreak, the role of the DoD and the U.S. African Command in controlling EVD is described. MATERIALS AND METHODS: A descriptive method design was used to collect and analyze all available Ebola outbreak literature using the PubMed database. An initial literature search was conducted by searching for, obtaining, and reading original source articles on all major global Ebola outbreaks. To conduct a focused search, we used initial search terms "Ebola outbreak," "Ebola virus disease," "Ebola response," "Ebola countermeasures," and also included each country's name where Ebola cases are known to have occurred. From the 4,673 unique articles obtained from this search and subsequent article title review, 307 articles were identified for potential inclusion. Following abstract and article review, 45 original source articles were used to compile the history of significant Ebola outbreaks. From this compilation, articles focused on each respective subsection of this review to delineate and describe the history of EVD and response, identifying fundamental changes, were obtained and incorporated. RESULTS: We present known Ebola virus and disease attributes, including a general description, seasonality and location, transmission capacity, clinical symptoms, surveillance, virology, historical EVD outbreaks and response, international support for Ebola outbreak response, U.S. DoD support, medical countermeasures supporting outbreak response, remaining gaps to include policy limitations, regional instability, climate change, migration, and urbanization, public health education and infrastructure, and virus persistence and public awareness. CONCLUSIONS: The health and societal impacts of EVD on Africa has been far-reaching, with about 35,000 cases and over 15,000 deaths, with small numbers of cases spreading globally. However, the history of combatting EVD reveals that there is considerable hope for African nations to quickly and successfully respond to Ebola outbreaks, through use of endemic resources including Africa CDC and African Partner Outbreak Response Alliance and the U.S. African Command with greater DoD reachback. Although there remains much to be learned about the Ebola virus and EVD including whether the potential for novel strains to become deadly emerging infections, invaluable vaccines, antivirals, and public health measures are now part of the resources that can be used to combat this disease.

State Responses of Several Classes of Linear Systems Based on Fundamental Matrices.

State responses for several classes of linear systems are investigated in this article. The involved systems include state-delayed linear systems, and high-order linear systems. At first, the single-fundamental-matrix-based approach is extended to these systems, and their state responses are expressed by their fundamental matrices (FMs). In addition, the multiple-FMs-based approach is presented for these systems. Based on a group of FMs, the state responses for the considered time-invariant systems are derived. For the considered time-variant systems, their state responses are explicitly expressed by their transition matrices. As an application of the fundamental-matrix-based approach, a stabilizing control law is designed for a class of high-order fully actuated continuous-time linear systems with a single input-delay.

Nitroreductase-responsive nanoparticles for in situ fluorescence imaging and synergistic antibacterial therapy of bacterial keratitis.

As bacterial keratitis progresses rapidly, prompt intervention is necessary. Current diagnostic processes are time-consuming and invasive, leading to improper antibiotics for treatment. Therefore, innovative strategies for diagnosing and treating bacterial keratitis are urgently needed. In this study, Cu2-xSe@BSA@NTRP nanoparticles were developed by loading nitroreductase-responsive probes (NTRPs) onto Cu2-xSe@BSA. These nanoparticles exhibited integrated fluorescence imaging and antibacterial capabilities. In vitro and in vivo experiments showed that the nanoparticles produced responsive fluorescence signals in bacteria within 30 min due to an interaction between the released NTRP and bacterial endogenous nitroreductase (NTR). When combined with low-temperature photothermal therapy (PTT), the nanoparticles effectively eliminated E. coli and S. aureus, achieved antibacterial efficacy above 95% and facilitated the re-epithelialization process at the corneal wound site in vivo. Overall, the Cu2-xSe@BSA@NTRP nanoparticles demonstrated potential for rapid, noninvasive in situ diagnosis, treatment, and visualization assessment of therapy effectiveness in bacterial keratitis.

Multifunctional polyaniline modified calcium alginate aerogel membrane with antibacterial, oil-water separation, dye and heavy metal ions removal properties for complex water purification.

With the rapid development of urbanization, the discharge of industrial wastewater has led to increasingly critical water pollution issues. Additionally, heavy metals, organic dyes, microorganisms and oil pollution often coexist and have persistence and harmfulness. Developing materials that can treat these complex pollutants simultaneously has important practical significance. In this study, a calcium alginate-based aerogel membrane (PANI@CA membrane) was prepared by spraying, polymerization, Ca2+ cross-linking and freeze-drying using aniline and sodium alginate as raw materials. Oil-water emulsion can be separated by PANI@CA membrane only under gravity, and the separation efficiency was as high as 99 %. At the same time, the membrane can effectively intercept or adsorb organic dyes and heavy metal ions. The removal rates of methylene blue and Congo red were above 92 % and 63 % respectively even after ten times of cyclic filtration. The removal rate of Pb2+ was up to 95 %. In addition, PANI@CA membrane shows excellent photothermal conversion ability, and it can effectively kill Staphylococcus aureus under 808 nm laser irradiation. PANI@CA membrane has the advantages of low cost, simple preparation, good stability and high recycling ability, and has potential application prospects in wastewater treatment.

Correction: A Y1 receptor ligand synergized with a P-glycoprotein inhibitor improves the therapeutic efficacy of multidrug resistant breast cancer.

Correction for 'A Y1 receptor ligand synergized with a P-glycoprotein inhibitor improves the therapeutic efficacy of multidrug resistant breast cancer' by Yinjie Wang et al., Biomater. Sci., 2019, 7, 4748-4757, https://doi.org/10.1039/C9BM00337A.

Heartland Virus Disease-An Underreported Emerging Infection.

First recognized 15 years ago, Heartland virus disease (Heartland) is a tickborne infection contracted from the transmission of Heartland virus (HRTV) through tick bites from the lone star tick (Amblyomma americanum) and potentially other tick species. Heartland symptoms include a fever <100.4 °F, lethargy, fatigue, headaches, myalgia, a loss of appetite, nausea, diarrhea, weight loss, arthralgia, leukopenia and thrombocytopenia. We reviewed the existing peer-reviewed literature for HRTV and Heartland to more completely characterize this rarely reported, recently discovered illness. The absence of ongoing serosurveys and targeted clinical and tickborne virus investigations specific to HRTV presence and Heartland likely contributes to infection underestimation. While HRTV transmission occurs in southern and midwestern states, the true range of this infection is likely larger than now understood. The disease's proliferation benefits from an expanded tick range due to rising climate temperatures favoring habitat expansion. We recommend HRTV disease be considered in the differential diagnosis for patients with a reported exposure to ticks in areas where HRTV has been previously identified. HRTV testing should be considered early for those matching the Heartland disease profile and nonresponsive to initial broad-spectrum antimicrobial treatment. Despite aggressive supportive therapy, patients deteriorating to sepsis early in the course of the disease have a very grim prognosis.

Peptide-Functionalized Inorganic Oxide Nanomaterials for Solid Cancer Imaging and Therapy.

The diagnosis and treatment of solid tumors have undergone significant advancements marked by a trend toward increased specificity and integration of imaging and therapeutic functions. The multifaceted nature of inorganic oxide nanomaterials (IONs), which boast optical, magnetic, ultrasonic, and biochemical modulatory properties, makes them ideal building blocks for developing multifunctional nanoplatforms. A promising class of materials that have emerged in this context are peptide-functionalized inorganic oxide nanomaterials (PFIONs), which have demonstrated excellent performance in multifunctional imaging and therapy, making them potential candidates for advancing solid tumor diagnosis and treatment. Owing to the functionalities of peptides in tumor targeting, penetration, responsiveness, and therapy, well-designed PFIONs can specifically accumulate and release therapeutic or imaging agents at the solid tumor sites, enabling precise imaging and effective treatment. This review provides an overview of the recent advances in the use of PFIONs for the imaging and treatment of solid tumors, highlighting the superiority of imaging and therapeutic integration as well as synergistic treatment. Moreover, the review discusses the challenges and prospects of PFIONs in depth, aiming to promote the intersection of the interdisciplinary to facilitate their clinical translation and the development of personalized diagnostic and therapeutic systems by optimizing the material systems.

A Contrast-Enhanced Tri-Modal MRI Technique for High-Performance Hypoxia Imaging of Breast Cancer.

Personalized radiotherapy strategies enabled by the construction of hypoxia-guided biological target volumes (BTVs) can overcome hypoxia-induced radioresistance by delivering high-dose radiotherapy to targeted hypoxic areas of the tumor. However, the construction of hypoxia-guided BTVs is difficult owing to lack of precise visualization of hypoxic areas. This study synthesizes a hypoxia-responsive T1 , T2 , T2 mapping tri-modal MRI molecular nanoprobe (SPION@ND) and provides precise imaging of hypoxic tumor areas by utilizing the advantageous features of tri-modal magnetic resonance imaging (MRI). SPION@ND exhibits hypoxia-triggered dispersion-aggregation structural transformation. Dispersed SPION@ND can be used for routine clinical BTV construction using T1 -contrast MRI. Conversely, aggregated SPION@ND can be used for tumor hypoxia imaging assessment using T2 -contrast MRI. Moreover, by introducing T2 mapping, this work designs a novel method (adjustable threshold-based hypoxia assessment) for the precise assessment of tumor hypoxia confidence area and hypoxia level. Eventually this work successfully obtains hypoxia tumor target and accurates hypoxia tumor target, and achieves a one-stop hypoxia-guided BTV construction. Compared to the positron emission tomography-based hypoxia assessment, SPION@ND provides a new method that allows safe and convenient imaging of hypoxic tumor areas in clinical settings.

Oxygen Vacancy Defect Enhanced NIR-II Photothermal Performance of BiOxCl Nanosheets for Combined Phototherapy of Cancer Guided by Multimodal Imaging.

Narrow photo-absorption range and low carrier utilization are significant barriers that restrict the antitumor efficiency of 2D bismuth oxyhalide (BiOX, X = Cl, Br, I) nanosheets (NSs). Introducing oxygen vacancy (OV) defects can expand the absorption range and improve carrier utilization, which are crucial but also challenging. In this study, a series of BiOxCl NSs with different OV defect concentrations (x = 1, 0.7, 0.5) is developed, which shows full spectrum absorption and strong absorption in the second near-infrared region (NIR-II). Density functional theory calculations are utilized to calculate the crystal structure and density states of BiOxCl, which confirm that part of the carriers is separated by OV enhanced internal electric field to improve carrier utilization. The carriers without redox reaction can be trapped in the OV, leading to great majority of photo-generated carriers promoting the photothermal performance. Triggered by single NIR-II (1064 nm), BiOxCl NSs' bidirectional efficient utilization of carriers achieves synchronously combined phototherapy, leading to enhanced tumor ablation and multimodal diagnostic in vitro and vivo. It is thus believed that this work provides an innovative strategy to design and construct nanoplatforms of indirect band gap semiconductors for clinical phototheranostics.

Janus mesoporous organosilica/platinum nanomotors for active treatment of suppurative otitis media.

We report a Janus mesoporous organosilica/platinum (MOS/Pt) nanomotor for active targeted treatment of suppurative otitis media, as a new type of multi-functional ear drop. The efficient propulsion of MOS/Pt nanomotors in hydrogen peroxide ear-cleaning drops significantly improves their binding efficiency with Staphylococcus aureus and enhances their antibacterial efficacy.

Quantification and biological evaluation of ZnxFe3-xO4 nanoparticle stiffness in a drug delivery system of MCF-7 cancer cells.

The delivery of nanoparticles (NPs) to tumors remains challenging despite significant advancements in drug delivery technologies. Addressing this issue requires the establishment of quantitative and reliable criteria to evaluate the cellular absorption of NPs. The mechanical characteristics of NPs and their interaction with cells play a crucial role in cellular drug delivery by influencing cellular internalization. In particular, NPs' stiffness has emerged as a key factor affecting cellular uptake and viability. In this study, we synthesized ZnxFe3-xO4 NPs with varying Zn doping concentrations and conducted an extensive measurement process to investigate the impact of NP stiffness on cellular uptake and the viability of cancerous cells. Initially, the stiffness of the NPs was measured using two methods: single-molecule force spectrometry of atomic force microscopy (SMFS-AFM) and cation distribution as chemical structure analysis. The influence of NP stiffness on intracellular behavior was examined by assessing cellular uptake and viability at different time points during the incubation period. The results obtained from both stiffness measurement methods exhibited consistent trends. NPs with higher stiffness exhibited enhanced cellular uptake but exhibited reduced cellular viability compared to the lower-stiffness NPs. Our findings provide valuable insights into the influence of Zn doping concentration on the mechanical properties of ZnxFe3-xO4 NPs and their consequential impacts on cellular internalization. This study contributes to an improved comprehension of the mechanisms underlying cellular uptake and facilitates advancements in the field of drug transport, thereby enhancing the efficiency of NP-based drug delivery.

Highly-Efficient Gallium-Interference Tumor Therapy Mediated by Gallium-Enriched Prussian Blue Nanomedicine.

Prussian blue (PB)-based nanomedicines constructed from metal ion coordination remain restricted due to their limited therapeutic properties, and their manifold evaluation complexity still needs to be unraveled. Owing to the high similarities of its ionic form to iron (Fe) and the resulting cellular homeostasis disruption performance, physiologically unstable and low-toxicity gallium (Ga) has garnered considerable attention clinically as an anti-carcinogen. Herein, Ga-based nanoparticles (NPs) with diverse Ga contents are fabricated in one step using PB with abundant Fe sites as a substrate for Ga substitution, which aims to overcome the deficiencies of both and develop an effective nanomedicine. A systematic comparison of their physicochemical properties effectively reveals the saturated Ga introduction state during the synthesis process, further identifying the most Ga-enriched PB NPs with a substitution content of >50% as a nanomedicine for subsequent exploration. It is verified that the Ga interference mechanisms mediated by the most Ga-enriched PB NPs are implicated in metabolic disorders, ionic homeostasis disruption, cellular structure dysfunction, apoptosis, autophagy, and target activation of the mammalian target of the rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways. This study provides significant guidance on exploiting clinically approved agents for Ga interference and lays the foundation for the next generation of PB-based theranostic agents.

Biodegradable hollow mesoporous bimetallic nanoreactors to boost chemodynamic therapy.

As an endogenous catalytic treatment, chemodynamic therapy (CDT) was attracting considerable attention, but the weak catalytic efficiency of Fenton agents and the non-degradation of nanocarriers severely limited its development. In this work, a biodegradable bimetallic nanoreactor was developed for boosting CDT, in which Fe-doped hollow mesoporous manganese dioxide (HMnO2) was selected as nanocarrier, and the Fe/HMnO2@DOX-GOD@HA nanoprobe was constructed by loading doxorubicin (DOX) and modifying glucose oxidase (GOD) and hyaluronic acid (HA). The glutathione (GSH) responsive degradation of HMnO2 promoted the release of DOX, by which the release rate significantly increased to 96.6%. Moreover, by the GSH depletion, the reduction of Mn2+/Fe2+ achieved strong bimetallic Fenton efficiency, and the hydroxyl radicals (·OH) generation was further enhanced using the self-supplying H2O2 of GOD. Through the active targeting recognition of HA, the bimetallic nanoreactor significantly enriched the tumor accumulation, by which the enhanced antitumor efficacy was realized. Thus, this work developed biodegradable bimetallic nanoreactor by consuming GSH and self-supplying H2O2, and provided a new paradigm for enhancing CDT.

Strategies for utilizing covalent organic frameworks as host materials for the integration and delivery of bioactives.

Covalent organic frameworks (COFs), a new and developing class of porous framework materials, are considered a type of promising carrier for the integration and delivery of bioactives, which have diverse fascinating merits, such as a large specific surface area, designable and specific porosity, stable and orderly framework structure, and various active sites. However, owing to the significant differences among bioactives (including drugs, proteins, nucleic acid, and exosomes), such as size, structure, and physicochemical properties, the interaction between COFs and bioactives also varies. In this review, we firstly summarize three strategies for the construction of single or hybrid COF-based matrices for the delivery of cargos, including encapsulation, covalent binding, and coordination bonding. Besides, their smart response release behaviors are also categorized. Subsequently, the applications of cargo@COF biocomposites in biomedicine are comprehensively summarized, including tumor therapy, central nervous system (CNS) modulation, biomarker analysis, bioimaging, and anti-bacterial therapy. Finally, the challenges and opportunities in this field are briefly discussed.

A D-Y Shaped Neuropeptide Y Mimetic Peptide-Dye Self-Assembly with Maximal Emission Beyond 1300 nm and Glioma Mitochondrial Activity Modulation.

Neuropeptide Y (NPY), as one of the most abundant neuropeptides known, is widely distributed in the central and peripheral nervous system. However, most of the reported NPY-mimetic peptides are hard to cross the blood-brain barrier, target glioma mitochondria, and achieve self-assembly nanostructure in situ. Here, based on the α-helix structure of the novel chiral NPY-mimetic peptides D/LNPY(14), a Y-shaped peptide is designed with the sequences that can be recognized by enterokinase and achieved nanofibers conversion in glioma cell mitochondria. Coupling the Y-shaped NPY-mimetic peptide with the NIR-II fluorophore IR1048, a red-shifting of the fluorescence spectrum beyond 1300 nm is achieved through self-assembly. After the self-assembly in glioma mitochondria, the formed nanofibers can promote intracellular mitochondrial ROS production and extend the NIR-II fluorescence imaging time to at least 7 days in vivo. This work for the first time endows the self-assembly of α-helical-based chiral NPY-mimetic peptides, providing a novel strategy for glioma subcellular regulation enhanced antitumor treatment guided by NIR-II fluorescence imaging.

Polydopamine nanomaterials and their potential applications in the treatment of autoimmune diseases.

The conventional treatment methods used for the management of autoimmune diseases (ADs) have limited efficacy and also exhibit significant side effects. Thus, identification of novel strategies to improve the efficacy and safety of ADs treatment is urgently required. Overactivated immune response and oxidative stress are common characteristics associated with ADs. Polydopamine (PDA), as a polymer material with good antioxidant and photothermal conversion properties, has displayed useful application potential against ADs. In addition, PDA possesses good biosafety, simple preparation, and easy functionalization, which is conducive for the pharmacological development of PDA nanomaterials with clinical transformation prospects. Here, we have first reviewed the preparation of PDA, the different functional integration strategies of PDA-based biomaterials, and their potential applications in ADs. Next, the mechanism of action of PDA in ADs has been elaborated in detail. Finally, the application opportunities and challenges linked with PDA nanomaterials for ADs treatment are discussed. This review is contributed to design reasonable and effective PDA nanomaterials for the diagnosis and treatment of ADs.