A Mild Hyperthermia Hollow Carbon Nanozyme as Pyroptosis Inducer for Boosted Antitumor Immunity.

The immune checkpoint blockade (ICB) antibody immunotherapy has demonstrated clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors is suppressed by deficient tumor immunogenicity and immunosuppressive tumor microenvironments. Pyroptosis, a form of programmed cell death, can release tumor antigens, activate effective tumor immunogenicity, and improve the efficiency of ICB, but efficient pyroptosis for tumor treatment is currently limited. Herein, we show a mild hyperthermia-enhanced pyroptosis-mediated immunotherapy based on hollow carbon nanozyme, which can specifically amplify oxidative stress-triggered pyroptosis and synchronously magnify pyroptosis-mediated anticancer responses in the tumor microenvironment. The hollow carbon sphere modified with iron and copper atoms (HCS-FeCu) with multiple enzyme-mimicking activities has been engineered to induce cell pyroptosis via the radical oxygen species (ROS)-Tom20-Bax-Caspase 3-gasdermin E (GSDME) signaling pathway under light activation. Both in vitro and in vivo antineoplastic results confirm the superiority of HCS-FeCu nanozyme-induced pyroptosis. Moreover, the mild photothermal-activated pyroptosis combining anti-PD-1 can enhance antitumor immunotherapy. Theoretical calculations further indicate that the mild photothermal stimulation generates high-energy electrons and enhances the interaction between the HCS-FeCu surface and adsorbed oxygen, facilitating molecular oxygen activation, which improves the ROS production efficiency. This work presents an approach that effectively transforms immunologically "cold" tumors into "hot" ones, with significant implications for clinical immunotherapy.

Targeting the stimulator of interferon genes (STING) in breast cancer.

Breast cancer has a high occurrence rate globally and its treatment has demonstrated clinical efficacy with the use of systemic chemotherapy and immune checkpoint blockade. Insufficient cytotoxic T lymphocyte infiltration and the accumulation of immunosuppressive cells within tumours are the primary factors responsible for the inadequate clinical effectiveness of breast cancer treatment. The stimulator of interferon genes (STING) represents a pivotal protein in the innate immune response. Upon activation, STING triggers the activation and enhancement of innate and adaptive immune functions, resulting in therapeutic benefits for malignant tumours. The STING signalling pathway in breast cancer is influenced by various factors such as deoxyribonucleic acid damage response, tumour immune microenvironment, and mitochondrial function. The use of STING agonists is gaining momentum in breast cancer research. This review provides a comprehensive overview of the cyclic guanosine monophosphate-adenosine monophosphate synthase-STING pathway, its agonists, and the latest findings related to their application in breast cancer.

Cascaded Nanozyme with In Situ Enhanced Photothermal Capacity for Tumor-Specific and Self-Replenishing Cancer Therapy.

Reactive oxygen species (ROS)-involved tumor therapeutic strategy, chemodynamic therapy (CDT), has attracted extensive research interest in the scientific community. However, the therapeutic effect of CDT is insufficient and unsustainable owing to the limited endogenous H2 O2 level in the tumor microenvironment. Here, peroxidase (POD)-like RuTe2 nanozyme with the immobilization of glucose oxidase (GOx) and allochroic 3,3',5,5'-tetramethylbenzidine (TMB) molecule have been synthesized to construct RuTe2 -GOx-TMB nanoreactors (RGT NRs) as cascade reaction systems for tumor-specific and self-replenishing cancer therapy. GOx in sequential nanocatalysts can effectively deplete glucose in tumor cells. Meanwhile, a sustainable supply of H2 O2 for subsequent Fenton-like reactions catalyzed by RuTe2 nanozyme is achieved in response to the mild acidic tumor microenvironment. Through this cascade reaction, highly toxic hydroxyl radicals (·OH) are produced, which can further oxidize TMB to trigger tumor-specific "turn-on" photothermal therapy (PTT). In addition, PTT and massive ROS can stimulate the tumor immune microenvironment and activate the systematic anti-tumor immune responses, exerting a notable effect on hindering tumor recurrence and metastasis. This study paves a promising paradigm for synergistic starvation therapy, PTT, and CDT cancer therapy with high efficiency.

Nitrogen-Centered Lactate Oxidase Nanozyme for Tumor Lactate Modulation and Microenvironment Remodeling.

Designing nanozymes that match natural enzymes have always been an attractive and challenging goal. In general, researchers mainly focus on the construction of metal centers and the control of non-metallic ligands of nanozyme to regulate their activities. However, this is not applicable to lactate oxidase, i.e., flavoenzymes with flavin mononucleotide (FMN)-dependent pathways. Herein, we propose a coordination strategy to mimic lactate oxidase based on engineering the electronic properties at the N center by modulating the Co number near N in the Cox-N nanocomposite. Benefitting from the manipulated coordination fields and electronic structure around the electron-rich N sites, Co4N/C possesses a precise recognition site for lactate and intermediate organization and optimizes the absorption energies for intermediates, leading to superior oxidation of the lactate α-C-sp(3)-H bond toward ketone. The optimized nanozyme delivers much improved anticancer efficacy by reversing the high lactate and the immunosuppressive state of the tumor microenvironment, subsequently achieving excellent tumor growth and distant metastasis inhibition. The developed Co4N/C NEs open a new window for building a bridge between chemical catalysis and biocatalysis.

Tea Polyphenol Liposomes Overcome Gastric Mucus to Treat Helicobacter Pylori Infection and Enhance the Intestinal Microenvironment.

Infection with Helicobacter pylori (Hp) is one of the leading causes of stomach cancer. The ability to treat Hp infection is hampered by a lack of stomach gastric acid environment. This work introduces a nanoliposome that can rapidly adjust the gastric acid environment to ensure a drug's optimal efficacy. We introduce CaCO3@Fe-TP@EggPC nanoliposomes (CTE NLs) that are composed of Fe3+ and tea polyphenols (TPs) forming complexes on the surface of internal CaCO3 and then with lecithin producing a phospholipid bilayer on the polyphenols' outer surface. Through the action of iron-TP chelate, the phospholipid layer can fuse with the bacterial membrane to eliminate Hp. Furthermore, CaCO3 can promptly consume the excessive gastric acid, ensuring an ideal operating environment for the chelate. TPs, on the other hand, can improve the inflammation and gut microbes in the body. The experimental results show that CTE NLs can quickly consume protons in the stomach and reduce the bacterial burden by 1.2 orders of magnitude while reducing the inflammatory factors in the body. The biosafety evaluation revealed that nanoliposomes have good biocompatibility and provide a new strategy for treating Hp infection.

A Cascade Nanozyme with Amplified Sonodynamic Therapeutic Effects through Comodulation of Hypoxia and Immunosuppression against Cancer.

The tumor microenvironment (TME) featured by immunosuppression and hypoxia is pivotal to cancer deterioration and metastasis. Thus, regulating the TME to improve cancer cell ablation efficiency has received extensive interest in oncotherapy. However, to reverse the immunosuppression and alleviate hypoxia simultaneously in the TME are major challenges for effective cancer therapy. Herein, a multifunctional platform based on Au nanoparticles and a carbon dots modified hollow black TiO2 nanosphere (HABT-C) with intrinsic cascade enzyme mimetic activities is prepared for reversing immunosuppression and alleviating hypoxia in the TME. The HABT-C NPs possess triple-enzyme mimetic activity to act as self-cascade nanozymes, which produce sufficient oxygen to alleviate hypoxia and generate abundant ROS. The theoretical analysis demonstrates that black TiO2 facilitates absorption of H2O and O2, separation of electron-holes, and generation of ROS, consequently amplifying the sonodynamic therapy (SDT) efficiency. Specifically, HABT-C exhibits favorable inhibition of immunosuppressive mediator expression, along with infiltrating of immune effector cells into the TME and reversing the immunosuppression in the TME. As a result, HABT-C can effectively kill tumor cells via eliciting immune infiltration, alleviating hypoxia, and improving SDT efficiency. This cascade nanozyme-based platform (HABT-C@HA) will provide a strategy for highly efficient SDT against cancer by modulation of hypoxia and immunosuppression in the TME.

NIR-II Responsive Hydrogel as an Angiogenesis Inhibition Agent for Tumor Microenvironment Reprogramming.

Regulation of angiogenesis is a great challenge for effective anticancer therapy. Generally, anti-angiogenic therapies are focused on inhibition of inducers involved in pro-angiogenic communication pathways. Despite the great potential of anti-angiogenic therapy, engineering efficient angiogenesis inhibition agents (AIAs) is still a formidable challenge, since most anti-angiogenic therapies are limited due to the cancer recurrence via compensatory expression of different angiogenic mediators. Herein, we present a new strategy of near-infrared-II (NIR-II) responsive hydrogel AIAs, constructed by incorporation of nitric oxide (NO) precursor (BNN6) and 2D WO2.9 nanosheets within hydrogel (WB@hydrogel). Because of the defect/2D engineering, the bandgap of the WO2.9 nanosheets narrows, which extends the absorption to the NIR-II region. It offers a favorable NIR-II controlled manner for NO generation through irradiation time and light intensity. The continuous supply of NO can activate the expression of wild-type p53 protein and further reverse the transcriptional expression of pro- and anti-angiogenic factors of the tumor microenvironment (TME), subsequently alternating pro-angiogenic TME to anti-angiogenic TME. In the murine tumor model, this method achieved high tumor growth inhibition (TGI) rate and excellent anti-recurrence efficiency.

Case Report: Noninvasive Clinical Intervention of REBACIN® on Histologic Regression of High Grade Cervical Intraepithelial Neoplasia.

High-risk human papillomavirus (hrHPV) persistent infection is the major cause of cervical cancer. Clinical intervention of hrHPV-associated high-grade squamous intraepithelial lesion (HSIL) is critical to prevent cervical cancer, and current treatment is surgery (an invasive therapy). However, some patients refuse to do so for an afraid of potential adverse effects on future fertility or other concerns which creates a critical need for development of non-invasive therapeutic strategies. Here, we report for the first time the cases of non-invasive intervention with REBACIN®, a proprietary antiviral biologics, in clinical treatment of HSIL. From 12,958 visiting patients assessed for eligibility, 18 HSIL-patients with cervical intraepithelial neoplasia-grade 2, positive of both diffused overexpression of p16 and high-risk HPV were enrolled in this non-invasive clinical intervention mainly due to concerns of future fertility. REBACIN® was administered intravaginally every other day for 3 months (one-course) except during menstrual period, and were followed up for 6-36 months for the examination of high-risk HPV DNA, cervical cytology, and histopathology. After one to three course treatments, most cases (16/18) displayed both the regression from HSIL (CIN2) to normal cervical cytology and clearance of high-risk HPV infection. Further studies demonstrated REBACIN® significantly suppressed HPV16 E7 oncoprotein expression in a human cervical cancer cell line, which is consistent with previous finding that REBACIN® inhibits the growth of tumors induced by expression of E6/E7 oncogenes of either HPV16 or HPV18. This report indicates REBACIN® as a novel effective non-invasive clinical intervention for HSIL-patients as well for high-risk HPV persistent infection, providing a new clinical option for the non-invasive treatment of hrHPV-associated high-grade squamous intraepithelial lesion, which is worthy of further research on clinical validation and application.

Inside-mode indium oxide/carbon nanotubes for efficient carbon dioxide electroreduction by suppressing hydrogen evolution.

The hydrogen evolution reaction is a huge challenge for CO2 electroreduction. Herein, an inside-mode indium oxide/carbon nanotube compound (MWCNTs@In2O3) is developed to maximize the catalytic effect and suppress hydrogen evolution, its HCOOH selectivity can reach up to 92.2% at -16.8 mA cm-2, which is more efficient than In2O3.

Design of well-defined shell-core covalent organic frameworks/metal sulfide as an efficient Z-scheme heterojunction for photocatalytic water splitting.

Development of a covalent-organic framework (COF)-based Z-scheme heterostructure is a promising strategy for solar energy driven water splitting, but the construction of a COF-based Z-scheme heterostructure with well-defined architecture, large contact area and intimate contact interfaces is scarce. Herein, we fabricated a direct Z-scheme heterostructure COF-metal sulfide hybrid (T-COF@CdS) with shell-core architecture by self-polymerization of 1,3,5-benzenetricarboxaldehyde and 2,4,6-tris(4-aminophenyl)-1,3,5-triazine in situ on CdS. The formed C-S chemical bonding between T-COF and CdS could provide a very tight and stable interface. Owing to the properly staggered band alignment, strong interfacial interaction and large interfacial contact area between T-COF and CdS, a Z-scheme route for charge separation and transfer is realized, resulting in electron accumulation in CdS for H2O reduction. The obtained Z-scheme heterostructure T-COF@CdS-3 exhibits a high apparent quantum efficiency of 37.8% under 365 nm monochromatic light irradiation, and long-term stability arising from shell-core structures in which the T-COF shell protects the catalytic centers of CdS against deactivation, as well as acts as oxidation sites to avoid the photocorrosion of CdS. This work provides a strategy for the construction of a shell-core direct Z-scheme heterostructure photocatalyst for water splitting with high performance.

In situ sprayed NIR-responsive, analgesic black phosphorus-based gel for diabetic ulcer treatment.

The treatment of diabetic ulcer (DU) remains a major clinical challenge due to the complex wound-healing milieu that features chronic wounds, impaired angiogenesis, persistent pain, bacterial infection, and exacerbated inflammation. A strategy that effectively targets all these issues has proven elusive. Herein, we use a smart black phosphorus (BP)-based gel with the characteristics of rapid formation and near-infrared light (NIR) responsiveness to address these problems. The in situ sprayed BP-based gel could act as 1) a temporary, biomimetic "skin" to temporarily shield the tissue from the external environment and accelerate chronic wound healing by promoting the proliferation of endothelial cells, vascularization, and angiogenesis and 2) a drug "reservoir" to store therapeutic BP and pain-relieving lidocaine hydrochloride (Lid). Within several minutes of NIR laser irradiation, the BP-based gel generates local heat to accelerate microcirculatory blood flow, mediate the release of loaded Lid for "on-demand" pain relief, eliminate bacteria, and reduce inflammation. Therefore, our study not only introduces a concept of in situ sprayed, NIR-responsive pain relief gel targeting the challenging wound-healing milieu in diabetes but also provides a proof-of-concept application of BP-based materials in DU treatment.

A NIR-II light responsive hydrogel based on 2D engineered tungsten nitride nanosheets for multimode chemo/photothermal therapy.

A hydrogel drug cargo based on 2D tungsten nitride nanosheets was fabricated. It exhibits stable NIR-II responsive photothermal properties and drug release behaviour. Moreover, this hydrogel shows excellent tumour ablation efficiency in vivo via NIR-II triggered multiple chemo/photothermal therapy.

Multifunctional two dimensional Bi2Se3 nanodiscs for combined antibacterial and anti-inflammatory therapy for bacterial infections.

A multifunctional platform based on two-dimensional nanomaterials for combined antibacterial and anti-inflammatory therapy is developed. Bi2Se3 nanodiscs selectively eradicate Gram-positive bacteria with a low risk of drug resistance. Moreover, Bi2Se3 nanodiscs with antioxidant activity relieve intracellular oxidative stress of macrophages to suppress inflammation caused by bacterial infections.

REBACIN® as a noninvasive clinical intervention for high-risk human papillomavirus persistent infection.

The development of highly sensitive HPV-genotyping tests has opened the possibility of treating HPV-infected women before high-grade lesions appear. The lack of efficient intervention for persistent high-risk HPV infection necessitates the need for development of novel therapeutic strategy. Here we demonstrate that REBACIN®, a proprietary antiviral biologics, has shown potent efficacy in the clearance of persistent HPV infections. Two independent parallel clinical studies were investigated, which a total of 199 patients were enrolled and randomly divided into a REBACIN®-test group and a control group without treatment. The viral clearance rates for the REBACIN® groups were 61.5% (24/39) and 62.5% (35/56), respectively, for the two independent parallel studies. In contrast, the nontreatment groups showed self-clearance rates at 20.0% (8/40) and 12.5% (8/64). We further found that REBACIN® was able to significantly repress the expression of HPV E6 and E7 oncogenes in TC-1 and Hela cells. The two viral genes are well known for the development of high-grade premalignancy lesion and cervical cancer. In a mouse model, REBACIN® was indicated to notably suppress E6/E7-induced tumor growth, suggesting E6 and E7 oncogenes as a potential target of REBACIN®. Taken together, our studies shed light into the development of a novel noninvasive therapeutic intervention for clearance of persistent HPV infection with significant efficacy.

Protein-Metal-Ion Networks: A Unique Approach toward Metal Sulfide Nanoparticles Embedded In Situ in Nanocomposites.

Nanoscale metal sulfides are of tremendous potential in biomedicine. Generally, the properties and performances of metal sulfide nanoparticles (NPs) are highly related to their structures, sizes and morphologies. Recently, a strategy of using sulfur-containing protein-metal-ion networks for preparing metal sulfide embedded nanocomposites was proposed. Within the networks, proteins can play multiple roles to drive the transformation of these networks into protein-encapsulated metal sulfide NPs with ultrasmall size and defined structure (as both a template and a sulfur provider) or metal sulfide NP-protein hydrogels with injecting and self-healing properties (as a template, a sulfur provider, and a gelator) in a controlled manner. In this Concept, the synthesis strategy, the formation mechanism, and the biomedical applications of the gained nanocomposites are presented. Moreover, the challenges and opportunities of using protein-metal ion networks to construct functional materials for biomedical applications are analyzed.

Highly sensitive fluorescent detection of p53 protein based on DNA functionalized Fe3O4 nanoparticles.

The accurate quantification of p53 protein expression level is of great importance for cancer diagnosis. Here, a highly sensitive fluorescent sensor based on DNA functionalized magnetic nanoparticles was developed for the detection of p53 protein expression. Instead of a monoclonal antibody, a consensus DNA was employed to capture p53 protein. Meanwhile the fluorescent dye tethered DNA was used as the signal output instead of enzyme tagged nanoparticle or antibody. Consequently, our developed method is cost-effective for both the p53 capture and detection by compared with the conventional immunoassay. The biosensor developed by the above strategy was used to quantitatively detect p53, which yields a detection limit of 8 p.M. with the linear range of 50 p.M. to 2 nM. The sensitive for specific p53 detection was achieved due to the facile magnetic separation from the complex condition, and the reduced non-specific absorption effect by dextran. Moreover, the method is able to measure p53 from real cell lysate without extensive sample pretreatment/separation. The developed p53 biosensor has high sensitivity, good selectivity and reliable accuracy. It demonstrates great potential in clinical cancer diagnosis and early detection of cancer.

Biomimetic nanothylakoids for efficient imaging-guided photodynamic therapy for cancer.

Biomimetic nanothylakoids, which are constructed from the thylakoid membrane of vegetable leaves, show high efficiency in tumor microenvironment modulation and photodynamic antitumor therapy under near infrared fluorescence guidance. Furthermore, their outstanding biosafety, facile preparation and low cost make nanothylakoids suitable for further clinical applications.

Two dimensional semiconductors for ultrasound-mediated cancer therapy: the case of black phosphorus nanosheets.

With black phosphorus (BP) as an example, the first two-dimensional (2D) semiconductor based sonosensitizer (Au@BP nanohybrids) was fabricated. Under ultrasound irradiation, Au@BP nanohybrids can generate 1O2 in deep tissues and eradicate tumors with high efficacy. This platform paves the way for the application of 2D semiconductors in sonodynamic cancer therapy.

MOF-Templated Fabrication of Hollow Co4N@N-Doped Carbon Porous Nanocages with Superior Catalytic Activity.

Metallic Co4N catalysts have been considered as one of the most promising non-noble materials for heterogeneous catalysis because of their high electrical conductivity, great magnetic property, and high intrinsic activity. However, the metastable properties seriously limit their applications for heterogeneous water phase catalysis. In this work, a novel Co-metal-organic framework (MOF)-derived hollow porous nanocages (PNCs) composed of metallic Co4N and N-doped carbon (NC) were synthesized for the first time. This hollow three-dimensional (3D) PNC catalyst was synthesized by taking advantage of Co-MOF as a precursor for fabricating 3D hollow Co3O4@C PNCs, along with the NH3 treatment of Co-oxide frames to promote the in situ conversion of Co-MOF to Co4N@NC PNCs, benefiting from the high intrinsic activity and electron conductivity of the metallic Co4N phase and the good permeability of the hollow porous nanostructure as well as the efficient doping of N into the carbon layer. Besides, the covalent bridge between the active Co4N surface and PNC shells also provides facile pathways for electron and mass transport. The obtained Co4N@NC PNCs exhibit excellent catalytic activity and stability for 4-nitrophenol reduction in terms of low activation energy (Ea = 23.53 kJ mol-1), high turnover frequency (52.01 × 1020 molecule g-1 min-1), and high apparent rate constant (kapp = 2.106 min-1). Furthermore, its magnetic property and stable configuration account for the excellent recyclability of the catalyst. It is hoped that our finding could pave the way for the construction of other hollow transition metal-based nitride@NC PNC catalysts for wide applications.

Marriage of artificial catalase and black phosphorus nanosheets for reinforced photodynamic antitumor therapy.

Two dimensional (2D) semiconducting nanomaterials have shown great potential for antitumor therapy. However, their clinical applications are seriously hampered by the tumour microenvironments. Bearing this in mind, we propose to improve the performance of 2D semiconducting nanomaterials using artificial catalase. In this work, we decorate black phosphorus (BP) nanosheets with Pt nanoparticles (NPs) through an in situ growth strategy. Pt NPs as artificial catalases can efficiently decompose the accumulated H2O2 in tumours to relieve tumour hypoxia, and thereafter improve the photodynamic antitumor activity of BP nanosheets. This work paves a new avenue for the functionalization of 2D semiconducting nanomaterials, which will promote the development of 2D semiconductor based nanodrugs.