Application of exosomes in tumor immunity: recent progresses.

Exosomes are small extracellular vesicles secreted by cells, ranging in size from 30 to 150 nm. They contain proteins, nucleic acids, lipids, and other bioactive molecules, which play a crucial role in intercellular communication and material transfer. In tumor immunity, exosomes present various functions while the following two are of great importance: regulating the immune response and serving as delivery carriers. This review starts with the introduction of the formation, compositions, functions, isolation, characterization, and applications of exosomes, and subsequently discusses the current status of exosomes in tumor immunotherapy, and the recent applications of exosome-based tumor immunity regulation and antitumor drug delivery. Finally, current challenge and future prospects are proposed and hope to demonstrate inspiration for targeted readers in the field.

Nano-optogenetic CAR-T Cell Immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy emerges as an effective cancer treatment. However, significant safety concerns remain, such as cytokine release syndrome (CRS) and "on-target, off-tumor" cytotoxicity, due to a lack of precise control over conventional CAR-T cell activity. To address this issue, a nano-optogenetic approach has been developed to enable spatiotemporal control of CAR-T cell activity. This system is comprised of synthetic light-sensitive CAR-T cells and upconversion nanoparticles acting as an in situ nanotransducer, allowing near-infrared light to wirelessly control CAR-T cell immunotherapy.

Dynamic monitoring of serum tumor markers as prognostic factors in patients with advanced non-small-cell lung cancer treated with first-line immunotherapy: a multicenter retrospective study.

Background: To date, no specific studies have reported the use of dynamic serum tumor markers (STMs) as prognostic factors in patients with advanced non-small-cell lung cancer (NSCLC) who receive first-line immunotherapy. Therefore, it is unclear whether STMs can be used as a prognostic factor for first-line immunotherapy in advanced NSCLC. Objectives: To elucidate the role of STMs in monitoring immunotherapy response in advanced NSCLC. Patients were treated with first-line programmed cell death-1/programmed cell death ligand-1 inhibitors at four Chinese centers. Design: This was a multicenter retrospective study. Methods: Blood samples were collected at baseline and after 6-8 weeks of treatment. Computed tomography scans were used to evaluate treatment efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Post-treatment drops in STMs [Serum carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125)] were decreased ⩾20% (Group C) over baseline was used as cutoff level for defining a marker response. If STMs were increased by ⩾20% after treatment, the therapeutic effect was limited (Group A). Patients with STM changes between a 20% increase or decrease were enrolled in Group B. In univariate and multivariate stepwise Cox regression analyses, STMs and RECIST responses were analyzed for their impact on progression-free survival (PFS) and overall survival (OS). Results: The analysis included 716 patients. By multivariate analysis, CEA, NSE, CYFRA21-1, CA19-9, and CA125 (Group A versus Group B and Group A versus Group C) were associated with significant differences in PFS. Similar results were observed in the OS analysis. Similar results were observed in the adenocarcinoma subgroup analyses. In squamous cell carcinoma subgroup analyses, there was no statistical difference in PFS (p = 0.147) or OS (p = 0.068) between Group A and Group B for CA125. Conclusion: The increase and decrease in serum levels of STMs might be reliable prognostic factors for immunotherapy efficacy in NSCLC patients.

Collagen-EGCG Combination Synergistically Prevents UVB-Induced Skin Photoaging in Nude Mice.

Ultraviolet (UV) radiation is a major cause of skin photoaging through generating excessive oxidative stress and inflammation. One of the strategies is to use photo-chemoprotectors, such as natural products with antioxidant and anti-inflammatory properties, to protect the skin from photo damage. The present study investigates the photoprotective potentials of topical administration of unhydrolyzed collagen, epigallocatechin gallate (EGCG), and their combination against ultraviolet B (UVB)-induced photoaging in nude mice. It is found that both the solo and combined pretreatments could recover UVB-induced depletion of antioxidative enzymes, including superoxide dismutase and glutathione peroxidase (GSH-Px), as well as an increase of lipid peroxide malondialdehyde and inflammatory tumor necrosis factor-α. Meanwhile, the UVB-stimulated skin collagen degradation is attenuated significantly with drug treatments, which is evidenced by expression analysis of matrix metalloproteinase-1 and hydroxyproline. Additionally, the mouse skin histology shows that the drug-pretreated groups possess decreased epidermis thickness and normal collagen fiber structure of the dermis layer. These results demonstrate that both EGCG and collagen can protect the skin against UVB-induced skin photoaging. Synergistically, the combination of them shows the maximum prevention to skin damage, showing its potential in the application of anti-photoaging formulation products.

TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells.

DNA methylation deregulation at partially methylated domains (PMDs) represents an epigenetic signature of aging and cancer, yet the underlying molecular basis and resulting biological consequences remain unresolved. We report herein a mechanistic link between disrupted DNA methylation at PMDs and the spatial relocalization of H3K9me3-marked heterochromatin in aged hematopoietic stem and progenitor cells (HSPCs) or those with impaired DNA methylation. We uncover that TET2 modulates the spatial redistribution of H3K9me3-marked heterochromatin to mediate the upregulation of endogenous retroviruses (ERVs) and interferon-stimulated genes (ISGs), hence contributing to functional decline of aged HSPCs. TET2-deficient HSPCs retain perinuclear distribution of heterochromatin and exhibit age-related clonal expansion. Reverse transcriptase inhibitors suppress ERVs and ISGs expression, thereby restoring age-related defects in aged HSPCs. Collectively, our findings deepen the understanding of the functional interplay between DNA methylation and histone modifications, which is vital for maintaining heterochromatin function and safeguarding genome stability in stem cells.

Expanding PROTACtable genome universe of E3 ligases.

Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce degradation by the ubiquitin-proteasome system (UPS) offer new opportunities to engage targets that remain challenging to be inhibited by conventional small molecules. One fundamental element in the degradation process is the E3 ligase. However, less than 2% amongst hundreds of E3 ligases in the human genome have been engaged in current studies in the TPD field, calling for the recruiting of additional ones to further enhance the therapeutic potential of TPD. To accelerate the development of PROTACs utilizing under-explored E3 ligases, we systematically characterize E3 ligases from seven different aspects, including chemical ligandability, expression patterns, protein-protein interactions (PPI), structure availability, functional essentiality, cellular location, and PPI interface by analyzing 30 large-scale data sets. Our analysis uncovers several E3 ligases as promising extant PROTACs. In total, combining confidence score, ligandability, expression pattern, and PPI, we identified 76 E3 ligases as PROTAC-interacting candidates. We develop a user-friendly and flexible web portal ( https://hanlaboratory.com/E3Atlas/ ) aimed at assisting researchers to rapidly identify E3 ligases with promising TPD activities against specifically desired targets, facilitating the development of these therapies in cancer and beyond.

Comparison of first-line immunotherapy efficacy between advanced lung squamous cell carcinoma and pulmonary lymphoepithelioma-like carcinoma: A propensity score matching multicenter study.

Background: Compared with other lung squamous cell carcinomas (LUSC), pulmonary lymphoepithelioma-like carcinoma (pLELC) is closely associated with Epstein-Barr virus (EBV) infections with a unique molecular profile and immune microenvironment. This study was thus established to compare the treatment response and effectiveness of immunotherapy between pLELC and LUSC. Material and Methods: We enrolled 31 patients with pLELC and 116 with LUSC receiving first-line immunotherapy at three centers in China and compared the treatment response and effectiveness of immunotherapy. Propensity score matching (PSM) was used to balance the differences in baseline data between the two groups. Results: Before PSM, progression-free survival and overall survival were longer in the pLELC group than in the LUSC group (progression-free survival: hazard ratio (HR), 1.67, 95% CI: 1.05-2.63, P = 0.028; overall survival: HR, 1.90, 95% CI: 1.06-3.40, P = 0.028). This remained unchanged after PSM (progression-free survival: HR, 1.79, 95% CI: 1.02-3.15, P = 0.044; overall survival: HR, 2.20; 95% CI: 1.10-4.37, P = 0.022). Conclusion: pLELC showed a clinically meaningful survival benefit compared with traditional LUSC following immunotherapy. Subsequent studies should consider the role of the EBV in the tumor immune microenvironment of pLELC.

Optogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy.

The cGAS-STING signaling pathway has emerged as a promising target for immunotherapy development. Here, we introduce a light-sensitive optogenetic device for control of the cGAS/STING signaling to conditionally modulate innate immunity, called 'light-inducible SMOC-like repeats' (LiSmore). We demonstrate that photo-activated LiSmore boosts dendritic cell (DC) maturation and antigen presentation with high spatiotemporal precision. This non-invasive approach photo-sensitizes cytotoxic T lymphocytes to engage tumor antigens, leading to a sustained antitumor immune response. When combined with an immune checkpoint blocker (ICB), LiSmore improves antitumor efficacy in an immunosuppressive lung cancer model that is otherwise unresponsive to conventional ICB treatment. Additionally, LiSmore exhibits an abscopal effect by effectively suppressing tumor growth in a distal site in a bilateral mouse model of melanoma. Collectively, our findings establish the potential of targeted optogenetic activation of the STING signaling pathway for remote immunomodulation in mice.

Baseline serum tumor markers predict the survival of patients with advanced non-small cell lung cancer receiving first-line immunotherapy: a multicenter retrospective study.

BACKGROUND: This study aimed to investigate the association between baseline serum tumor markers (STMs) (carcinoembryonic antigen [CEA], neuron-specific enolase [NSE], cytokeratin-19 fragment [CYFRA21-1], carbohydrate antigen 19-9 [CA19-9], and carbohydrate antigen 125 [CA125]) and the efficacy of first-line immunotherapy in patients with advanced non-small cell lung cancer. METHODS: This multicenter retrospective study evaluated patients who received first-line immunotherapy between July 2017 and July 2022. The endpoints were progression-free survival (PFS) and overall survival (OS), as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. We divided the patients into three groups based on STM levels: Group A ≥ threefold upper limit of normal, threefold upper limit of normal > Group B > upper limit of normal, and Group C ≤ upper limit of normal. RESULTS: In total, 716 patients were included in this study. In Cox proportional hazards analyses, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung adenocarcinoma (LUAD). Except for CA19-9 level, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung squamous carcinoma (LUSC). Except for CEA and CA19-9 levels, the levels in Group A were independently associated with inferior PFS and OS in patients with LUAD and LUSC. CONCLUSIONS: Serum CEA, NSE, CYFRA21-1, and CA125 levels can predict PFS and OS in patients with LUAD and LUSC, and serum CA19-9 levels can predict PFS and OS in patients with LUAD. The higher the serum NSE, CYFRA21-1, and CA125 levels, the worse the PFS and OS in patients with LUAD and LUSC. In addition, the higher the serum CA19-9 level, the worse the OS in patients with LUAD.

Metformin as a booster of cancer immunotherapy.

Metformin, a biguanide antidiabetic, has been studied for its repurposing effects in oncology. Although a modest effect was observed in a single-agent regimen, metformin can synergize the anti-tumor effects of other modalities. The promising combination for cancer treatment is with immunotherapy. Despite high efficacy for some cancers, immunotherapy could be limited by modulation of the tumor immune microenvironment and the immune exhaustion of cytotoxic immune cells. Combining immunotherapy with metformin, thus, exerted a rescuing effect of immunotherapy and potentiated the anti-tumor effects of each other. Although not fully understood, metformin shows promoting effects of immunotherapy by several mechanisms. Those proposed mechanisms have been partially proven and are suggested for possible therapeutic strategies for cancer treatment. In this review, a state-of-the-art of metformin's boosting effects on immunotherapy is reviewed and discussed. The future directions for metformin research in preclinical and clinical immunotherapy are also suggested.

High glucose enhances the aggressiveness of lung adenocarcinoma via activating epidermal growth factor receptor/signal transducer and activator of transcription 3 pathways.

Epidemiological studies revealed hyperglycemia as a poor prognostic factor for lung adenocarcinoma with unclear molecular mechanisms. The present study thus aimed to investigate the effects of high glucose on the progression of lung adenocarcinoma and its underlying mechanisms. Lung adenocarcinoma cell lines, A549 and RERF-LC-KJ, were cultured in 5.6 mM glucose (normal glucose; NG) or 25 mM glucose (high glucose; HG) resembling euglycemia and hyperglycemia. Cells were examined for proliferation by the MTT assay, and migration-invasion using Transwell. The expressions of signaling proteins in epidermal growth factor receptor (EGFR) pathways and their downstream targets were investigated using Western blots. The effects of diabetes mellitus (DM) and hyperglycemia on lung adenocarcinoma growth in vivo were studied in streptozotocin-induced diabetic BALB/cAJcl-Nu/Nu mice and their nondiabetic counterparts. High glucose significantly promoted proliferation, migration, and invasion of lung adenocarcinoma cells compared with those in normal glucose (P<.05). Western blot analyses showed the increased ratio of pEGFR/EGFR in cells cultured in high glucose and subsequently activated the signal transducer and activator of transcription 3 (STAT3). Epithelial-mesenchymal (EMT) markers were also altered in lung adenocarcinoma cells in high glucose conditions, corresponding with increased migration and invasion abilities. Erlotinib, an EGFR inhibitor, significantly reversed high glucose-induced aggressive phenotypes confirming high glucose-enhancing lung adenocarcinoma progression via the activation of EGFR. DM and hyperglycemia also promoted the growth of lung adenocarcinoma xenografts in vivo in which erlotinib significantly suppressed the growth of tumors (P<.05) suggesting EGFR inhibitor as an effective therapeutic agent for lung adenocarcinoma with DM.

A "light" touch on PI3K to interrogate cancer drug resistance.

In this issue of Cell Chemical Biology, Ueda et al. (2022) developed PPAP2 as an improved optogenetic tool to photo-induce PI3K signaling hyperactivation in cancer cells. They demonstrated that enhanced translation of tumor necrosis factor alpha-induced protein 8 (TNFAIP8) might explain PI3K hyperactivation-associated resistance toward DNA damaging anti-cancer alkylating agents.

Harnessing natural killer cells to develop next-generation cellular immunotherapy.

Cellular immunotherapy harnesses the body's own immune system to fight cancer by using engineered T cells, macrophages, or natural killer (NK) cells. Compared to chimeric antigen receptor T (CAR-T) cells that are commonly used to treat hematological malignancies, CAR-NK cells have shown remarkable therapeutic effectiveness while exhibiting enhanced safety, reduced risk of graft-versus-host disease, fewer side effects, and amplified antitumor efficacy. Preclinical trials have unveiled the high potential of adoptive CAR-NK cell therapy to curtail or even eliminate both hematological malignancies and solid tumors in animal models. We brought forth herein the design principle of CAR-NK cells, highlighted the latest progress in the preclinical testing and clinical trials of CAR-NK cells, briefly delved into discussed major roadblocks in CAR-NK therapy, and discussed potential solutions to surmount these challenges. Given the accelerated progress in both basic and translational studies on immune cell engineering, CAR-NK cell therapy promises to become a serious contender and important addition to the next-generation cell-based immunotherapy.

Nano-optogenetic immunotherapy.

Chimeric antigen receptor (CAR) T cell-based immunotherapy has been increasingly used in the clinic for cancer intervention over the past 5 years. CAR T-cell therapy takes advantage of genetically-modified T cells to express synthetic CAR molecules on the cell surface. To date, up to six CAR T cell therapy products have been approved by the Food and Drug Administration for the treatment of leukaemia, lymphoma, and multiple myeloma. In addition, hundreds of CAR-T products are currently under clinical trials to treat solid tumours. In both the fundamental research and clinical applications, CAR T cell immunotherapy has achieved exciting progress with remarkable remission or suppression of cancers. However, CAR T cell-based immunotherapy still faces significant safety issues, as exemplified by "on-target off-tumour" cytotoxicity due to lack of strict antigen specificity. In addition, uncontrolled massive activation of infused CAR T cells may create severe systemic inflammation with cytokine release syndrome and neurotoxicity. These challenges call for a need to combine nanotechnology and optogenetics with immunoengineering to develop spatiotemporally-controllable CAR T cells, which enable wireless photo-tunable activation of therapeutic immune cells to deliver personalised therapy in the tumour microenvironment.

Cyclin-Dependent Kinase 4/6 Inhibitors: A Potential Breakthrough Therapy for Malignancies of Gastrointestinal Tract.

Cancer is the leading cause of death worldwide for which effective treatments remain limited. This article aimed to critically review and discuss the potential of targeting cell cycle machineries as a vital tool for cancer treatment. Cyclin dependent kinase (CDK) 4/6 inhibitors were originally approved by the United State Food and Drug Administration (US FDA) for advanced-stage breast cancer treatment. The nearly double-prolonged survival time in patients who received CDK4/6 inhibitors are superior to the conventional chemotherapy or endocrine therapy alone and, thus, these medications have been designated a breakthrough therapy by the US FDA. The requirement of CDK4/6 in the progression of cancer cells, but probably dispensable in normal cells, makes CDK4/6 a popular target for cancer treatment. The effects of CDK4/6 inhibitors in cancer may also involve the tumor microenvironment in which the therapeutic effects are synergistically pronounced. These emerging roles, hence, prompt investigations regarding their therapeutic potential in other cancers, including gastrointestinal cancer. Many preclinical and clinical studies of CDK4/6 inhibitors in gastrointestinal cancers are underway and, as a result, several new potentials are gradually reported. Contrariwise, the primary effect of this drug group is arresting the cell cycle rather than inducing cell death. The efficacy of using CDK4/6 inhibitors as a single regimen in clinical practice is then limited. In this article, the effects of CDK4/6 inhibitors on the progression of gastrointestinal cancers, at both preclinical and clinical levels are reviewed. The future directions for research and the possibility of CDK4/6 inhibitors being "breakthrough therapy" for gastrointestinal cancers are also discussed.

Aberrant DNA hydroxymethylation reshapes transcription factor binding in myeloid neoplasms.

Epigenetic abnormalities in DNA hydroxymethylation (5hmC) have been detected in patients with myeloid neoplasms, suggesting that 5hmC might act as a valuable epigenetic mark to reflect the disease status of myeloid neoplasms. Here, we report systematic genome-wide mapping of the DNA hydroxymethylomes in over 70 patients with myeloid neoplasms. Our integrative analysis leads to the identification of distinct 5hmC signatures that can sensitively discriminate patients from healthy individuals. At the molecular level, we unveiled dynamic 5hmC changes within key transcription factor (e.g., the CEBP family) binding motifs that are essential for hematopoiesis and myeloid lineage specification. 5hmC redistribution was found to alter the genome-wide binding of CEBP-α, thereby reprogramming transcriptional outputs to affect leukemia cell survival and stemness. Taken together, we provide a comprehensive 5hmC atlas representative of myeloid neoplasms, which sets the stage for future exploration on the epigenetic etiology of hematological malignancies. Mechanistically, our study further furnishes important insights into how abnormal 5hmC distribution in patients directly interrupts the binding of transcription factors to reshape transcriptional landscapes and aggravate leukemogenesis.

METTL3 Is Associated With the Malignancy of Esophageal Squamous Cell Carcinoma and Serves as a Potential Immunotherapy Biomarker.

Methyltransferase-like 3 (METTL3) is an RNA methyltransferase mediating N6 methyladenosine (m6A) modification. Its role in cancer pathogenesis and progression has attracted increasing attention. However, the immunological role, possible immune mechanism, and clinical significance of METTL3 in esophageal squamous cell carcinoma (ESCC) remain to be confirmed. The Tumor Genome Atlas (TCGA) provided clinical and transcriptome sequencing data for this study (162 tumor tissue samples and 11 normal tissue samples), while the Immunology Database and Analysis Portal (immport, https://www.immport.org/home) provided 2483 immune-related genes. METTL3 was substantially expressed in ESCC and linked to poor prognosis in ESCC, according to the findings. Functional analysis revealed that METTL3 is mainly involved in chromosomal homologous recombination and DNA mismatch repair processes, which could be potential mechanisms for tumor disease development and progression. Analysis on the TISIDB website shows that effector memory CD8 T cells, NK cells, neutrophils and other cells are highly correlated with METTL3 expression. We screened immune genes associated with METTL3 by Spearman's analysis and performed functional analysis. These immune genes were mostly linked with immune processes, such as cytokine receptors, the MAPK signaling pathway, and natural killer cell-mediated cytotoxicity, indicating that METTL3 is a key molecule in the immune regulation of esophageal cancer. In addition, based on METTL3-related immune genes, we separated the patients into several subgroups and constructed a prognostic prediction model consisting of six immune genes. As an independent prognostic indicator for ESCC, the risk score of this model can be employed. A nomogram was also developed to accurately evaluate individual prognoses based on clinical indicators and risk scores. In summary, this study suggests that METTL3 is not only a potential pathogenic molecule for esophageal carcinogenesis and progression but also a potential biological marker for forecasting ESCC patient prognosis and could serve as a basis for clinical decision making.

STIM1 Deficiency In Intestinal Epithelium Attenuates Colonic Inflammation and Tumorigenesis by Reducing ER Stress of Goblet Cells.

BACKGROUND & AIMS: As an indispensable component of store-operated Ca2+ entry, stromal interaction molecule 1 (STIM1) is known to promote colorectal cancer and T-cell-mediated inflammatory diseases. However, whether the intestinal mucosal STIM1 is involved in inflammatory bowel diseases (IBDs) is unclear. This study aimed to investigate the role of intestinal epithelial STIM1 in IBD. METHODS: Inflammatory and matched normal intestinal tissues were collected from IBD patients to investigate the expression of STIM1. Intestinal epithelium-specific STIM1 conditional knockout mice (STIM1ΔIEC) were generated and induced to develop colitis and colitis-associated colorectal cancer. The mucosal barrier, including the epithelial barrier and mucus barrier, was analyzed. The mechanisms by which STIM1 regulate goblet cell endoplasmic reticulum stress and apoptosis were assessed. RESULTS: STIM1 could regulate intestinal epithelial homeostasis. STIM1 was augmented in the inflammatory intestinal tissues of IBD patients. In dextran sodium sulfate-induced colitis, STIM1 deficiency in intestinal epithelium reduced the loss of goblet cells through alleviating endoplasmic reticulum stress induced by disturbed Ca2+ homeostasis, resulting in the maintenance of the integrated mucus layer. These effects prevented commensal bacteria from contacting and stimulating the intestinal epithelium of STIM1ΔIEC mice and thereby rendered STIM1ΔIEC mice less susceptible to colitis and colitis-associated colorectal cancer. In addition, microbial diversity in dextran sodium sulfate-treated STIM1ΔIEC mice slightly shifted to an advantageous bacteria, which further protected the intestinal epithelium. CONCLUSIONS: Our results establish STIM1 as a crucial regulator for the maintenance of the intestinal barrier during colitis and provide a potential target for IBD treatment.

Ten-Eleven Translocation Ablation Impairs Cardiac Differentiation of Mouse Embryonic Stem Cells.

Ten-eleven Translocation (TET) dioxygenases mediated DNA methylation oxidation plays an important role in regulating the embryonic stem cells (ESCs) differentiation. Herein, we utilized a CRISPR/Cas9 based genome editing method to generate single, double, and triple Tet-deficient mouse ESCs (mESCs) and differentiated these cells toward cardiac progenitors. By using emerald green fluorescent protein (GFP; emGFP) expression under the control of Nkx2.5 promoter as marker for cardiac progenitor cells, we discovered that Tet1 and Tet2 depletion significantly impaired mESC-to-cardiac progenitor differentiation. Single-cell RNA-seq analysis further revealed that Tet deletion resulted in the accumulation of mesoderm progenitors to hamper cardiac differentiation. Re-expression of the Tet1 catalytic domain (Tet1CD) rescued the differentiation defect in Tet-triple knockout mESCs. Dead Cas9 (dCas9)-Tet1CD mediated loci-specific epigenome editing at the Hand1 loci validated the direct involvement of Tet-mediated epigenetic modifications in transcriptional regulation during cardiac differentiation. Our study establishes that Tet-mediated epigenetic remodeling is essential for maintaining proper transcriptional outputs to safeguard mESC-to-cardiac progenitor differentiation.

Metallic phase enabling MoS2 nanosheets as an efficient sonosensitizer for photothermal-enhanced sonodynamic antibacterial therapy.

Two-dimensional (2D) transition metal dichalcogenide (TMD) nanosheets (e.g., MoS2) with metallic phase (1T or 1T´ phase) have been proven to exhibit superior performances in various applications as compared to their semiconducting 2H-phase counterparts. However, it remains unclear how the crystal phase of 2D TMD nanosheets affects their sonodynamic property. In this work, we report the preparation of MoS2 nanosheets with different phases (metallic 1T/1T´ or semiconducting 2H) and exploration of its crystal-phase effect on photothermal-enhanced sonodynamic antibacterial therapy. Interestingly, the defective 2D MoS2 nanosheets with high-percentage metallic 1T/1T´ phase (denoted as M-MoS2) present much higher activity towards the ultrasound-induced generation of reactive oxygen species (ROS) as compared to the semiconducting 2H-phase MoS2 nanosheets. More interestingly, owing to its metallic phase-enabled strong absorption in the near-infrared-II (NIR-II) regime, the ultrasound-induced ROS generation performance of the M-MoS2 nanosheets can be further enhanced by the photothermal effect under a 1064 nm laser irradiation. Thus, after modifying with polyvinylpyrrolidone, the M-MoS2 nanosheets can be used as an efficient sonosensitizer for photothermal-enhanced sonodynamic bacterial elimination under ultrasound treatment combining with NIR-II laser irradiation. This study demonstrates that metallic MoS2 nanosheets can be used as a promising sonosensitizer for antibacterial therapy, which might be also promising for cancer therapies.