Infectious diseases, caused by the direct exposure of cellular or acellular pathogens, are found to be closely associated with multiple inflammation and immune responses, keeping one of the top threats to human health. As an indispensable trace element, Selenium (Se) plays important roles in antioxidant defence and redox state regulation along with a variety of specific metabolic pathways. In recent decades, with the development of novel nanotechnology, Selenium nanoparticles (Se NPs) emerged as a promising agent for biomedical uses due to their low toxicity, degradability and high bioavailability. Taking the advantages of the strong ability to trigger apoptosis or autophagy by regulating reactive oxygen species (ROS), Se NPs have been widely used for direct anticancer treatments and pathogen killing/clearance in host cells. With excellent stability and drug encapsulation capacity, Se NPs are now serving as a kind of powerful nano-carriers for anti-cancer, anti-inflammation and anti-infection treatments. Notably, Se NPs are also found to play critical roles in immunity regulations, such as macrophage and T effector cell activation, which thus provides new possibilities to achieve novel nano-immune synergetic strategy for anti-cancer and anti-infection therapies. In this review, we summarized the progress of preparation methods for Se NPs, followed by the advances of their biological functions and mechanisms for biomedical uses, especially in the field of anti-infection treatments. Moreover, we further provide some prospects of Se NPs in anti-infectious diseases, which would be helpful for facilitating their future research progress for anti-infection therapy.

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IntroductionAs a deadly disease induced by Mycobacterium tuberculosis (Mtb), tuberculosis remains one of the top killers among infectious diseases. The low intracellular Mtb killing efficiency of current antibiotics introduced the long duration anti-TB therapy in clinic with strong side effects and increased drug-resistant mutants. Therefore, the exploration of novel anti-TB agents with potent anti-TB efficiency becomes one of the most urgent issues for TB therapies. MethodsHere, we firstly introduced a novel method for the preparation of zinc oxide-selenium nanoparticles (ZnO-Se NPs) by the hybridization of zinc oxide and selenium to combine the anti-TB activities of zinc oxide nanoparticles and selenium nanoparticles. We characterized the ZnO-Se NPs by dynamic laser light scattering and transmission electron microscopy, and then tested the inhibition effects of ZnO-Se NPs on extracellular Mtb by colony-forming units (CFU) counting, bacterial ATP analysis, bacterial membrane potential analysis and scanning electron microscopy imaging. We also analyzed the effects of ZnO-Se NPs on the ROS production, mitochondrial membrane potential, apoptosis, autophagy, polarization and PI3K/Akt/mTOR signaling pathway of Mtb infected THP-1 macrophages. At last, we also tested the effects of ZnO-Se NPs on intracellular Mtb in THP-1 cells by colony-forming units (CFU) counting. ResultsThe obtained spherical core-shell ZnO-Se NPs with average diameters of 90 nm showed strong killing effects against extracellular Mtb, including BCG and the virulent H37Rv, by disrupting the ATP production, increasing the intracellular ROS level and destroying the membrane structures. More importantly, ZnO-Se NPs could also inhibit intracellular Mtb growth by promoting M1 polarization to increase the production of antiseptic nitric oxide and also promote apoptosis and autophagy of Mtb infected macrophages by increasing the intracellular ROS, disrupting mitochondria membrane potential and inhibiting PI3K/Akt/mTOR signaling pathway. DiscussionThese ZnO-Se NPs with synergetic anti-TB efficiency by combining the Mtb killing effects and host cell immunological inhibition effects were expected to serve as novel anti-TB agents for the development of more effective anti-TB strategy.

Bacterial infection remains one of the most dangerous threats to human health due to the increasing cases of bacterial resistance, which is caused by the extensive use of current antibiotics. Photothermal therapy (PTT) is similar to photodynamic therapy (PDT), but PTT can generate heat energy under the excitation of light of specific wavelength, resulting in overheating and damage to target cells or sites. Polydopamine (PDA) has been proved to show plenty of advantages, such as simple preparation, good photothermal conversion effects, high biocompatibility, and easy functionalization and adhesion. Taking these advantages, dopamine is widely used to synthesize the PDA nanosystem with excellent photothermal effects, good biocompatibility, and high drug loading ability, which therefore play more and more important roles for anticancer and antibacterial treatment. PDA nanosystem-mediated PTT has been reported to induce significant tumor inhibition, as well as bacterial killings due to PTT-induced hyperthermia. Moreover, combined with other cancer or bacterial inhibition strategies, PDA nanosystem-mediated PTT can achieve more effective tumor and bacterial inhibitions. In this review, we summarized the progress of preparation methods for the PDA nanosystem, followed by advances of their biological functions and mechanisms for PTT uses, especially in the field of antibacterial treatments. We also provided advances on how to combine PDA nanosystem-mediated PTT with other antibacterial methods for synergistic bacterial killings. Moreover, we further provide some prospects of PDA nanosystem-mediated PTT against intracellular bacteria, which might be helpful to facilitate their future research progress for antibacterial therapy.

: Tuberculosis (TB), induced by Mycobacterium tuberculosis (MTB), is a fatal infectious disease that kills millions of lives worldwide. The emergence of drug-resistant and multidrug-resistant cases is regarded as one of the most challenging threats to TB control due to the low cure rate. Therefore, TB and drug-resistant TB epidemics urge us to explore more effective therapies. The increasing knowledge of nanotechnology has extended to some nanomedicines for disease treatment in the clinic, which also provides novel possibilities for nano-based medicines for TB treatment. Zinc oxide nanoparticles (ZnO NPs) have gained increasing attention for anti-bacterial uses based on their strong ability to induce reactive oxidative species (ROS) and release bactericidal Zinc ions (Zn2+), which are expected to act as novel strategies for TB and drug-resistant TB treatment. Some active herbal medicines from plant extracts have been widely reported to show attractive anti-bacterial activity for infectious treatment, including TB. Here, we summarize the synthesis of ZnO NPs using plant extracts (green synthesized ZnO NPs) and further discuss their potentials for anti-TB treatments. This is the first review article discussing the anti–TB activity of ZnO NPs produced using plant extracts, which might contribute to the further applications of green synthesized ZnO NPs for anti-TB and drug-resistant TB treatment.

As an essential micronutrient, manganese plays an important role in the physiological process and immune process. In recent decades, cGAS-STING pathway, which can congenitally recognize exogenous and endogenous DNA for activation, has been widely reported to play critical roles in the innate immunity against some important diseases, such as infections and tumor. Manganese ion (Mn2+) has been recently proved to specifically bind with cGAS and activate cGAS-STING pathway as a potential cGAS agonist, however, is significantly restricted by the low stability of Mn2+ for further medical application. As one of the most stable forms of manganese, manganese dioxide (MnO2) nanomaterials have been reported to show multiple promising functions, such as drug delivery, anti-tumor and anti-infection activities. More importantly, MnO2 nanomaterials are also found to be a potential candidate as cGAS agonist by transforming into Mn2+, which indicates their potential for cGAS-STING regulations in different diseased conditions. In this review, we introduced the methods for the preparation of MnO2 nanomaterials as well as their biological activities. Moreover, we emphatically introduced the cGAS-STING pathway and discussed the detailed mechanisms of MnO2 nanomaterials for cGAS activation by converting into Mn2+. And we also discussed the application of MnO2 nanomaterials for disease treatment by regulating cGAS-STING pathway, which might benefit the future development of novel cGAS-STING targeted treatments based on MnO2 nanoplatforms.

Manganese (Mn), a nutrient inorganic trace element, is necessary for a variety of physiological processes of animal body due to their important roles in oxidative regulation effects and other aspects of activities. Moreover, manganese ion (Mn2+) has widely reported to be crucial for the regulations of different immunological responses, thus showing promising application as potential adjuvants and immunotherapeutics. Taking the advantages of Mn-based biological and immunological activities, Manganese dioxide nanoparticles (MnO2 NPs) are a new type of inorganic nanomaterials with numerous advantages, including simple preparation, low cost, environmental friendliness, low toxicity, biodegradable metabolism and high bioavailability. MnO2 NPs, as a kind of drug carrier, have also shown the ability to catalyze hydrogen peroxide (H2O2) to produce oxygen (O2) under acidic conditions, which can enhance the efficacy of radiotherapy, chemotherapy and other therapeutics for tumor treatment by remodeling the tumor microenvironment. More importantly, MnO2 NPs also play important roles in immune regulations both in innate and adaptive immunity. In this review, we summarize the biological activities of Manganese, followed by the introduction for the biological and medical functions and mechanisms of MnO2 NPs. What’s more, we emphatically discussed the immunological regulation effects and mechanisms of MnO2 NPs, as well as their potentials to serve as adjuvants and immunomodulators, which might benefit the development of novel vaccines and immunotherapies for more effective disease control.

Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains a top killer among infectious diseases. While Bacillus Calmette-Guerin (BCG) is the sole TB vaccine, the clumped-clustered features of BCG in intradermal immunization appear to limit both the BCG protection efficacy and the BCG vaccination safety. We hypothesize that engineering of clumped-clustered BCG into nanoscale particles would improve safety and also facilitate the antigen-presenting-cell (APC)’s uptake and the following processing/presentation for better anti-TB protective immunity. Here, we engineered BCG protoplasts into nanoscale membraned BCG particles, termed as “BCG-Nanocage” to enhance the anti-TB vaccination efficiency and safety. BCG-Nanocage could readily be ingested/taken by APC macrophages selectively; BCG-Nanocage-ingested macrophages exhibited better viability and developed similar antimicrobial responses with BCG-infected macrophages. BCG-Nanocage, like live BCG bacilli, exhibited the robust capability to activate and expand innate-like T effector cell populations of Vγ2+ T, CD4+ T and CD8+ T cells of rhesus macaques in the ex vivo PBMC culture. BCG-Nanocage immunization of rhesus macaques elicited similar or stronger memory-like immune responses of Vγ2Vδ2 T cells, as well as Vγ2Vδ2 T and CD4+/CD8+ T effectors compared to live BCG vaccination. BCG-Nanocage- immunized macaques developed rapidly-sustained pulmonary responses of Vγ2Vδ2 T cells upon Mtb challenge. Furthermore, BCG- and BCG-Nanocage- immunized macaques, but not saline controls, exhibited undetectable Mtb infection loads or TB lesions in the Mtb-challenged lung lobe and hilar lymph node at endpoint after challenge. Thus, the current study well justifies a large pre-clinical investigation to assess BCG-Nanocage for safe and efficacious anti-TB vaccination, which is expected to further develop novel vaccines or adjuvants. Graphical Abstract