TMEM232 promotes the inflammatory response in atopic dermatitis via the nuclear factor-κB and signal transducer and activator of transcription 3 signalling pathways.

BACKGROUND: Our group previously found that the transmembrane protein 232 (TMEM232) gene was associated with atopic dermatitis (AD) by genome-wide association study and fine mapping study. However, its function is unclear so far. OBJECTIVES: To investigate the roles and mechanisms of TMEM232 in AD. METHODS: The expression of TMEM232 was investigated in skin lesions of patients with AD, the MC903-induced AD mouse model, human primary keratinocytes and immortalized human keratinocyte cell line (HaCaT) cells stimulated with different inflammatory factors. The role of TMEM232 in AD was analysed in HaCaT cells and Tmem232 knockout (Tmem232-/-) mice. Tmem232-specific small interfering RNA (siRNA) was used to evaluate its therapeutic potential in the AD mouse model. RESULTS: The expression of TMEM232 was significantly increased in skin lesions of patients with AD, the MC903-induced AD mouse model and human primary keratinocytes and HaCaT cells stimulated with different inflammatory factors compared with controls. In the presence of MC903, Tmem232-/- mice exhibited significantly reduced dermatitis severity, mast-cell infiltration in the back, and expression of T-helper (Th)1 and Th2-related inflammatory factors in skin tissue compared with wild-type mice. In vitro and in vivo experiments further showed that upregulation of TMEM232 in AD exacerbated the inflammation response through activating the pathway of nuclear factor-κB and signal transducer and activator of transcription (STAT) 3, and was regulated by the interleukin-4/STAT6 axis, which formed a self-amplifying loop. Finally, topical application of Tmem232 siRNA markedly ameliorated AD-like lesions in the AD model. CONCLUSIONS: This study is the first to outline the function of TMEM232. It is involved in regulating inflammation in AD and may be a potential target for AD treatment.

Topical bismuth oxide-manganese composite nanospheres alleviate atopic dermatitis-like inflammation.

Atopic dermatitis (AD) is a common skin disease involving important immune mechanisms. There is an unmet need for a treatment for this condition. Herein, we focused on elucidating the role of Bi2-xMnxO3 nanospheres (BM) in alleviating skin inflammation in AD-like C57BL/6 mice. The BM was fabricated via sacrificial templates and its biosafety was systematically evaluated. The BM was applied topically to skin lesions of AD-like C57BL/6 mice. The phenotypic and histological changes in the skin were examined carefully. The responses of barrier proteins, inflammatory cytokines and cells to BM were evaluated in HaCaT cells and AD mouse models. The data demonstrated that BM treatment alleviated the AD phenotypes and decreased the level of inflammatory factors, while increasing the expression of the barrier proteins filaggrin/involucrin in the skin. BM effectively reduced the expression of phosphorylated STAT6, which in turn reduced the expression of GATA3, and further decreased the differentiation ratio of Th2 cells, thereby reducing the expression of IL-4. In conclusion, topical drug therapy with BM provides a safe and effective treatment modality for AD by reducing IL-4 and increasing barrier proteins.

A multifunctional composite hydrogel as an intrinsic and extrinsic coregulator for enhanced therapeutic efficacy for psoriasis.

BACKGROUND: Psoriasis is a chronic relapsing immunological skin disease characterized by multiple cross-talk inflammatory circuits which are relevantly associated with abnormal cross-reactivity between immune cells and keratinocytes (KCs). It may be inadequate to eradicate complicated pathogenesis only via single-mode therapy. To provide optimal combinatory therapeutics, a nanocomposite-based hydrogel was constructed by loading methotrexate (MTX) into ZnO/Ag to realize combined multiple target therapy of psoriasis. RESULTS: In this composite hydrogel, ZnO hybrid mesoporous microspheres were utilized both as drug carriers and reactive oxygen species (ROS)-scavenging nanoparticles. A proper amount of Ag nanoparticle-anchored ZnO nanoparticles (ZnO/Ag) was functionalized with inherent immunoregulatory property. The experiments showed that ZnO/Ag nanoparticles could exhibit a self-therapeutic effect that was attributed to reducing innate cytokine profiles by inactivating p65 in proinflammatory macrophages and abrogating secretion of adaptive cytokines in KCs by downregulating ROS-mediated STAT3-cyclin D1 signaling. A preferable antipsoriatic efficacy was achieved via topical administration of this hydrogel on the imiquimod (IMQ)-induced psoriasis mice model, demonstrating the superior transdermal delivery and combined enhancement of therapeutic efficacy caused by intrinsic nanoparticles and extrinsic MTX. CONCLUSION: This composite hydrogel could serve as a multifunctional, nonirritating, noninvasive and effective transcutaneous nanoagent against psoriasis.

Recent Development on Controlled Synthesis of Metal Sulfides Hollow Nanostructures via Hard Template Engaged Strategy: A Mini-Review.

In this mini-review, we highlighted the recent progresses in the controlled synthesis of metal sulfides hollow nanostructures via hard template technique. After a brief introduction about the formation mechanism of the inorganic hollow nanostructures via hard template technique, the discussions primarily focused on the emerging development of metal sulfides hollow nanostructures. Various synthetic strategies were summarized concerning the use of the hard template engaged strategies to fabricate various metal sulfides hollow nanostructures, such as hydrothermal method, solvothermal method, ion-exchange, sulfidation or calcination etc. Finally, the perspectives and summaries have been presented to demonstrate that a facile synthetic technique would be widely used to fabricate metal sulfides hollow nanostructures with multi-shells and components.

Engineering Hyaluronic Acid Microneedles Loaded with Mn2+ and Temozolomide for Topical Precision Therapy of Melanoma.

Topical therapy has received worldwide attention for in situ tumors owing to its higher efficacy of drug delivery. Herein, this work reports a dissolvable multifunctional hyaluronic acid microneedles (HMNs) patch coloaded with temozolomide (TMZ) and MnCl2 (TMZ/MnCl2@HMN) for chemoimmunotherapy of melanoma. HMNs can ensure the stability of TMZ over time, and exhibit fewer side effects with a localized release way. In particular, TMZ not only promotes dendritic cell maturation by triggering immunogenic cell death in tumor cells, but also induces DNA damage that can further enhance the Mn2+-activated cGAS-STING (stimulator of interferon genes pathway). As a result, the TMZ/MnCl2@HMN multifunctional platform significantly inhibits lung metastases for melanoma, providing a practical strategy for precision therapy of melanoma.

Urchin-like Fe3O4@Bi2S3 Nanospheres Enable the Destruction of Biofilm and Efficiently Antibacterial Activities.

Biofilm-associated infections (BAIs) have been considered a major threat to public health, which induce persistent infections and serious complications. The poor penetration of antibacterial agents in biofilm significantly limits the efficiency of combating BAIs. Magnetic urchin-like core-shell nanospheres of Fe3O4@Bi2S3 were developed for physically destructing biofilm and inducing bacterial eradication via reactive oxygen species (ROS) generation and innate immunity regulation. The urchin-like magnetic nanospheres with sharp edges of Fe3O4@Bi2S3 exhibited propeller-like rotation to physically destroy biofilm under a rotating magnetic field (RMF). The mild magnetic hyperthermia improved the generation of ROS and enhanced bacterial eradication. Significantly, the urchin-like nanostructure and generated ROS could stimulate macrophage polarization toward the M1 phenotype, which could eradicate the persistent bacteria with a metabolic inactivity state through phagocytosis, thereby promoting the recovery of implant infection and inhibiting recurrence. Thus, the design of magnetic-driven sharp-shaped nanostructures of Fe3O4@Bi2S3 provided enormous potential in combating biofilm infections.

Cancer cell membrane-coated upconversion nanoparticles/ZnxMn1-xS core-shell nanoparticles for targeted photodynamic and chemodynamic therapy of pancreatic cancer.

Oxidative stress induced by reactive oxygen species (ROS) is promising treatment approach for pancreatic ductal adenocarcinoma (PDAC), which is typically insensitive to conventional chemotherapy. In this study, BxPC-3 pancreatic cancer cell membrane-coated upconversion nanoparticles/ZnxMn1-xS core-shell nanoparticles (abbreviated as BUC@ZMS) were developed for tumor-targeted cancer therapy via synergistically oxidative stress and overcoming glutathione (GSH) overexpression. Using a combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT), the BUC@ZMS core-shell nanoparticles were able to elicit the death of pancreatic cancer cells through the high production of ROS. Additionally, the BUC@ZMS core-shell nanoparticles could deplete intracellular GSH and increase the sensitivity of tumor cells to oxidative stress. The in vivo results indicated that BUC@ZMS nanoparticles can accumulate specifically in tumor locations and suppress PDAC without generating obvious toxicity. Thus, it was determined that the as-prepared core-shell nanoparticles would be a viable treatment option for solid malignancies.

Multifunctional Au@AgBiS2 Nanoparticles as High-Efficiency Radiosensitizers to Induce Pyroptosis for Cancer Radioimmunotherapy.

Radiotherapy (RT), a widely used clinical treatment modality for cancer, uses high-energy irradiation for reactive oxygen species (ROS) production and DNA damage. However, its therapeutic effect is primarily limited owing to insufficient DNA damage to tumors and harmful effects on normal tissues. Herein, a core-shell structure of metal-semiconductors (Au@AgBiS2 nanoparticles) that can function as pyroptosis inducers to both kill cancer cells directly and trigger a robust anti-tumor immune against 4T1 triple-negative murine breast cancer and metastasis is rationally designed. Metal-semiconductor composites can enhance the generation of considerable ROS and simultaneously DNA damage for RT sensitization. Moreover, Au@AgBiS2 , a pyroptosis inducer, induces caspase-3 protein activation, gasdermin E cleavage, and the release of damage-associated molecular patterns. In vivo studies in BALB/c mice reveal that Au@AgBiS2 nanoparticles combined with RT exhibit remarkable antitumor immune activity, preventing tumor growth, and lung metastasis. Therefore, this core-shell structure is an alternative for designing highly effective radiosensitizers for radioimmunotherapy.

Bi2-xMnxO3 Nanospheres Engaged Radiotherapy with Amplifying DNA Damage.

Radiotherapy efficacy was greatly limited by hypoxia and overexpression of glutathione (GSH) in the tumor microenvironment (TME), which maintained the immunosuppressive microenvironment and promoted DNA repair. In this work, 4T1 cell membrane-coated Bi2-xMnxO3 nanospheres have been achieved via a facile protocol, which showed enhanced therapeutic efficacy for a combination of radiotherapy and immunotherapy. Bi2-xMnxO3 nanospheres showed appreciable performance in generating O2 in situ and depleting GSH to amplify DNA damage and remodel the tumor immunosuppressive microenvironment, thus enhancing radiotherapy efficacy. Cancer cell membrane-coated Bi2-xMnxO3 nanospheres (T@BM) prolonged blood circulation time and enriched the accumulation of the materials in the tumor. Meanwhile, the released Mn2+ could activate STING pathway-induced immunotherapy, resulting in the immune infiltration of CD8+ T cells on in situ mammary tumors and the inhibition of pulmonary nodules. As a result, approximately 1.9-fold recruitment of CD8+ T cells and 4.0-fold transformation of mature DC cells were observed compared with the phosphate-buffered saline (PBS) group on mammary tumors (in situ). In particular, the number of pulmonary nodules significantly decreased and the proliferation of pulmonary metastatic lesions was substantially inhibited, which provided a longer survival period. Therefore, T@BM exhibited great potential for the treatment of 4T1 tumors in situ and lung metastasis.

A tumour microenvironment-mediated Bi2-xMnxO3 hollow nanospheres via glutathione depletion for photothermal enhanced chemodynamic collaborative therapy.

Photothermal-enhanced chemodynamic therapy (CDT) has been attracting increasing attention for effective tumour treatment. Nevertheless, even though Mn-based nanostructures are promising CDT agents, their photothermal conversion capacities are not good enough for an ideal combination therapy. In this work, a bifunctional Bi2-xMnxO3 nanoplatform was developed, with tumour microenvironment (TME)-triggered photothermal therapy (PTT)-enhanced CDT, for a collaborative therapy for tumours. The doping of a small amount of Bi tuned the photothermal and CDT performance of Bi2-xMnxO3, thus promoting the photothermal conversion ability as well as accelerating the ˙OH generation. The existence of reductive Mn4+ could disrupt the internal tumour redox balance by enhancing glutathione (GSH) consumption to improve the CDT effect. Meanwhile, the mild photothermal effect could accelerate the depletion of GSH and the generation of ˙OH in the tumour region after laser irradiation, thus promoting the CDT effect. This manganese-based nanoplatform provides a good strategy for tumour therapy via TME-mediated PTT-enhanced CDT.

Phototherapy Using a Fluoroquinolone Antibiotic Drug to Suppress Tumor Migration and Proliferation and to Enhance Apoptosis.

In this work, a fluoroquinolone antibiotic drug (sparfloxacin (SP)) was selected as a chemotherapy drug and photosensitizer for combined therapy. A facile chemical process was developed to incorporate SP and upconversion nanoparticles (UCNPs) into the thermally sensitive amphiphilic polymer polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane). In vitro and in vivo experiments showed that 60% of the SP molecules can be released from the micelles of thermal-sensitive polymers using a 1 W cm-2 980 nm laser, and this successfully inhibits cell migration and metastasis by inhibiting type II topoisomerases in nuclei. Additionally, intracellular metal ions were chelated by SP to induce cancer cell apoptosis by decreasing the activity of superoxide dismutase and catalase. In particular, the fluoroquinolone molecules produced singlet oxygen (1O2) to kill cancer cells, and this was triggered by UCNPs when irradiation was performed with a 980 nm laser. Overall, SP retained a weak chemotherapeutic effect, achieved enhanced photosensitizer-like effects, and was able to repurpose old drugs to elevate the therapeutic efficacy against cancer, increase the specificity for suppressing tumor migration and proliferation, and enhance apoptosis.

Upconversion nanoparticles@AgBiS2 core-shell nanoparticles with cancer-cell-specific cytotoxicity for combined photothermal and photodynamic therapy of cancers.

UCNPs@AgBiS2 core-shell nanoparticles that AgBiS2 coated on the surface of upconversion nanoparticles (UCNPs) was successfully prepared through an ion exchange reaction. The photothermal conversion efficiency of AgBiS2 can be improved from 14.7% to 45% due to the cross relaxation between Nd ions and AgBiS2. The doping concentration of Nd ions played a critical role in the production of reactive oxygen species (ROS) and enhanced the photothermal conversion efficiency. The NaYF4:Yb/Er/Nd@NaYF4:Nd nanoparticles endows strong upconversion emissions when the doped concentration of Nd ions is 1% in the inner core, which excites the AgBiS2 shell to produce ROS for photodynamic therapy (PDT) of cancer cells. As a result, the as-prepared NaYF4:Yb/Er/Nd@NaYF4:Nd@AgBiS2 core-shell nanoparticles showed combined photothermal/photodynamic therapy (PTT/PDT) against malignant tumors. This work provides an alternative near-infrared light-active multimodal nanostructures for applications such as fighting against cancers.

Immunogenic Cell Death Augmented by Manganese Zinc Sulfide Nanoparticles for Metastatic Melanoma Immunotherapy.

Both T-cell deprivation and insufficient tumor immunogenicity seriously hinder the efficacy of immune-mediated tumor destruction in melanoma. In this work, an amphiphilic polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane) copolymer with a thermally sensitive flowable core (mPEG-b-PHEP) was chosen to incorporate IR780 dye and manganese zinc sulfide nanoparticles (ZMS) to form polymer micelles (denoted PPIR780-ZMS), which precisely controlled the release of ZMS after being triggered by near-infrared light (NIR). Mn2+-mediated chemodynamic therapy (CDT) by photothermal trigger boosted the generation of reactive oxygen species (ROS), making the PPIR780-ZMS smart bomblets in vivo. It was demonstrated that PPIR780-ZMS could maximize immunogenic cell death (ICD) in cancer, which is characterized by abundant damage-associated molecular pattern (DAMP) exposure. As a result, the cytotoxic T cells (CD8+) and helper T cells (CD4+) expanded and infiltrated the neoplastic foci, which further reprogrammed the suppressive tumor microenvironment (TME) against the primary tumor and pulmonary metastases with safe systemic cytokine expression. In addition, Mn2+-mediated cGAS-STING signaling pathway activation enhanced the antitumor immunity of this nanocomposite, providing a practical strategy for expanding the use of Mn-based nanostructures.

Interfacially Engineered ZnxMn1-xS@Polydopamine Hollow Nanospheres for Glutathione Depleting Photothermally Enhanced Chemodynamic Therapy.

Fenton-like reactions driven by manganese-based nanostructures have been widely applied in cancer treatment owing to the intrinsic physiochemical properties of these nanostructures and their improved sensitivity to the tumor microenvironment. In this work, ZnxMn1-xS@polydopamine composites incorporating alloyed ZnxMn1-xS and polydopamine (PDA) were constructed, in which the Fenton-like reactions driven by Mn ions can be tuned by a controllable release of Mn ions in vitro and in vivo. As a result, the ZnxMn1-xS@PDA exhibited good biocompatibility with normal cells but was specifically toxic to cancer cells. In addition, the shell thickness of PDA was carefully investigated to obtain excellent specific toxicity to cancer cells and promote synergistic chemodynamic and photothermal therapies. Overall, this work highlights an alternative strategy for fabricating high-performance, multifunctional composite nanostructures for a combined cancer treatment.

Ultrastable AgBiS2 Hollow Nanospheres with Cancer Cell-Specific Cytotoxicity for Multimodal Tumor Therapy.

Specific cytotoxicity for catalytic nanomedicine triggered by the tumor microenvironment (TME) has attracted increasing interest. In this work, we prepared AgBiS2 hollow nanospheres with narrow bandgaps via rapid precipitation in a weakly polar solvent, which lowered the intrinsic energy gap for the active production of highly reactive hydroxyl radicals (•OH), especially in the TME. The as-prepared AgBiS2 hollow nanospheres exhibited enhanced optical absorption and high photothermal conversion efficiency (44.2%). In addition, the hollow structured AgBiS2 nanospheres were found to have a peroxidase-mimicking feature to induce cancer cell-specific cytotoxicity while exhibiting negligible cytotoxicity toward normal cells, which might be attributed to the efficient production of highly reactive •OH originating from the overexpression H2O2 in the TME caused by surface catalysis. In particular, the cancer cell-specific cytotoxicity of the nanospheres was greatly enhanced both in vitro and in vivo upon irradiation with a near-infrared (NIR) laser (808 nm). The above-mentioned features of the hollow structured AgBiS2 will make it a promising candidate for tumor therapy.

Rod-based urchin-like hollow microspheres of Bi2S3: Facile synthesis, photo-controlled drug release for photoacoustic imaging and chemo-photothermal therapy of tumor ablation.

Hollow nanostructures have been evoked considerable attention owing to their intriguing hollow interior for important and potential applications in drug delivery, lithium battery, catalysis and etc. Herein, Bi2S3 hollow microspheres with rod-based urchin-like nanostructures (denoted as U-BSHM) were synthesized through a facile and rapid ion exchanging method using a particular hard template. The growth mechanism of the U-BSHM has been investigated and illustrated by the morphological evolution of the different samples at early stages. The obtained U-BSHM exhibited strong and wide UV-vis-NIR absorption ability and outstanding photothermal conversion efficiency. Thus, the U-BSHM can be used as spatio-temporal precisely controlled carrier by loading the mixture of 1-tetradecanol (phase change material, PCM) with melting point around 38 °C and hydrophilic chemotherapeutic doxorubicin hydrochloride (denoted as DOX) into the hollow interior to form (PCM + DOX)@Bi2S3 nanocomposites (denoted as PD@BS) for photoacoustic (PA) imaging and chemo-photothermal therapy of the tumors. When exposed to 808 nm near infrared light (NIR) laser irradiation, this nanocomposites could elevate the temperature of the surroundings by absorption and conversion of the NIR photons into heat energy, which inducing the triggered release of DOX from the hollow interior once the temperature reach up to the melting point of PCM. The killing efficiency of the chemo-photothermal therapy was systematically validated both in vitro and in vivo. In the meanwhile, the implanted tumor was completely restrained through PA imaging and combined therapies. Therefore, this kind of urchin-like hollow nanostructures would be used as important candidates for the multimodal bioimaging and therapy of tumors.

Fe, Co, Ni nanocrystals encapsulated in nitrogen-doped carbon nanotubes as Fenton-like catalysts for organic pollutant removal.

Magnetic metal M (M=Fe, Co, Ni) nanocrystals encapsulated in nitrogen-doped carbon nanotubes (M@N-C) were fabricated conveniently using dicyandiamide as a C/N precursor, and exhibited varying activities toward Fenton-like reaction. The surface morphology and structure of the M@N-C catalysts were characterized and an efficient catalytic degradation performance, high stability, and excellent reusability were observed. In addition, several operational factors, such as initial dye concentration, oxidant type (peroxymonosulfate, peroxydisulfate and H2O2) and dosage, reaction temperature, and dye type as well as stability of the composite were extensively evaluated in view of the practical applications. The results showed that various transition metals M significantly affected the structures and performances of the catalysts, and specially, their activity followed the order of Co>Fe>Ni in the presence of peroxymonosulfate. Moreover, HO⁡ and SO4(-) radicals participating in the process were evidenced using quenching experiments, and a rational mechanism was proposed based on a non-radical process and the free radical process. Control experiments revealed that the enhanced active sites were mainly ascribed to the synergistic effects between the metal nanocrystals and nitrogen-doped carbon. The findings of this study elucidated that encapsulation of nanocrystals in nitrogen-doped carbon nanotubes was an effective strategy to enhance the overall catalytic activity.