A Titanium Nitride Nanozyme for pH-Responsive and Irradiation-Enhanced Cascade-Catalytic Tumor Therapy.

Nanozyme-based catalytic tumor therapy is an emerging therapeutic method with high reactivity in response to tumor microenvironments (TMEs). To overcome the current limitations of deficient catalytic activity of nanozymes, we studied the contributing factors of enzymatic activity based on non-metallic-atom doping and irradiation. Nitrogen doping significantly enhanced the peroxidase activity of Ti-based nanozymes, which was shown experimentally and theoretically. Based on the excellent NIR-adsorption-induced surface plasmon resonance and photothermal effect, the enzymatic activity of TiN nanoparticles (NPs) was further improved under NIR laser irradiation. Hence, an acidic TME-responsive and irradiation-mediated cascade nanocatalyst (TLGp) is presented by using TiN-NP-encapsulated liposomes linked with pH-responsive PEG-modified glucose oxidase (GOx). The integration of pH-responsive GOx-mediated H2 O2 self-supply, nitrogen-doping, and irradiation-enhanced enzymatic activity of TiN NPs and mild-photothermal therapy enables an effective tumor inhibition by TLGp with minimal side effects in vivo.

Bismuth Sulfide Nanoflowers Facilitated miR339 Delivery to Overcome Stemness and Radioresistance through Ubiquitin-Specific Peptidase 8 in Esophageal Cancer.

Despite the superior efficacy of radiotherapy in esophageal squamous cell carcinoma (ESCC), radioresistance by cancer stem cells (CSCs) leads to recurrence, metastasis, and treatment failure. Therefore, it is necessary to develop CSC-based therapies to enhance radiotherapy. miR-339-5p (miR339) is involved in stem cell division and DNA damage checkpoint signaling pathways based on ESCC cohort. miR339 inhibited ESCC cell stemness and enhanced radiation-induced DNA damage by targeting USP8, suggesting that it acts as a potential CSC regulator and radiosensitizer. Considering the limited circulating periods and poor tumor-targeting ability of miRNA, a multifunctional nanoplatform based on bismuth sulfide nanoflower (Bi@PP) is developed to efficiently deliver miR339 and improve radioresistance. Intriguingly, Bi@PP encapsulates more miR339 owing to their flower-shaped structure, delivering more than 1000-fold miR339 into cells, superior to free miR339 alone. Besides being used as a carrier, Bi@PP is advantageous for dynamically monitoring the distribution of delivered miR339 in vivo while simultaneously inhibiting tumor growth. Additionally, Bi@PP/miR339 can significantly enhance radiotherapy efficacy in patient-derived xenograft models. This multifunctional platform, incorporating higher miRNA loading capacity, pH responsiveness, hypoxia relief, and CT imaging, provides another method to promote radiosensitivity and optimize ESCC treatment.

Hypoxia and pH co-triggered oxidative stress amplifier for tumor therapy.

To keep fast proliferation, tumor cells are exposed to higher oxidative stress than normal cells and they upregulate the amount of some antioxidants such as glutathione (GSH) against reactive oxygen species to maintain the balance. This phenomenon is severe in hypoxic tumor cells. Although researchers have proposed a series of treatment strategies based on regulating the intracellular reactive oxygen species level, few of them are related to the hypoxic tumor. Herein, a novel organic compound (PLC) was designed by using lysine as a bridge to connect two functional small molecules, a hypoxia-responsive nitroimidazole derivative (pimonidazole) and a pH-responsive cinnamaldehyde (CA) derivative. Then, the oxidative stress amplifying ability of PLC in hypoxic tumor cells was evaluated. The acidic microenvironment of tumor can trigger the release of CA to produce reactive oxygen species. Meanwhile, large amount of nicotinamide adenine dinucleotide phosphate (NADPH) can be consumed to decrease the synthesis of GSH during the bio-reduction process of the nitro group in PLC under hypoxic conditions. Therefore, the lethal effect of CA can be amplified for the decrease of GSH. Our results prove that this strategy can significantly enhance the therapeutic effect of CA in the hypoxic tumor cells.

Few-Layer Bismuthene for Checkpoint Knockdown Enhanced Cancer Immunotherapy with Rapid Clearance and Sequentially Triggered One-for-All Strategy.

As a conceptually attractive strategy, the use of immune checkpoint blockade antibodies to treat cancer is limited due to the restrained tumor-infiltrating lymphocytes (TILs), poor accumulation and penetration of antibodies, and deficient checkpoint blockade in malignancies. In this study, we describe a pH and mild photothermal sequentially triggered PD-L1 siRNA release nanosystem, based on monoelemental bismuthene, as a one-for-all strategy to realize enhanced tumor mild photothermal immunotherapy. Under manually controlled NIR irradiation, the bismuthene-based nanosystem simultaneously induces a tumor-enhanced pathological permeability and retention (EPPR) effect, increases TIL recruitment, and triggers programmed siRNA release, thereby amplifying anti-PD-L1 immunotherapy. In addition, the nanosystem's rapid removal through intestinal and renal clearance mitigates toxicity risk associated with long-term retention. In vivo antitumor experiments demonstrate that this bismuthene-based nanosystem is a promising and effective approach for "cold" tumor management.

Defect-Rich Adhesive Molybdenum Disulfide/rGO Vertical Heterostructures with Enhanced Nanozyme Activity for Smart Bacterial Killing Application.

Nanomaterials with intrinsic enzyme-like activities, namely "nanozymes," are showing increasing potential as a new type of broad-spectrum antibiotics. However, their feasibility is still far from satisfactory, due to their low catalytic activity, poor bacterial capturing capacity, and complicated material design. Herein, a facile synthesis of a defect-rich adhesive molybdenum disulfide (MoS2 )/rGO vertical heterostructure (VHS) through a one-step microwave-assisted hydrothermal method is reported. This simple, convenient but effective method for rapid material synthesis enables extremely uniform and well-dispersed MoS2 /rGO VHS with abundant S and Mo vacancies and rough surface, for a performance approaching the requirements of practical application. It is demonstrated experimentally and theoretically that the as-prepared MoS2 /rGO VHS possesses defect and irradiation dual-enhanced triple enzyme-like activities (oxidase, peroxidase, and catalase) for promoting free-radical generation, owing to much more active edge sites exposure. Meanwhile, the VHS-achieved rough surface exhibits excellent capacity for bacterial capture, with elevated reactive oxygen species (ROS) destruction through local topological interactions. As a result, optimized efficacy against drug-resistant Gram-negative and Gram-positive bacteria can be explored by such defect-rich adhesive nanozymes, demonstrating a simple but powerful way to engineered nanozymes for alternative antibiotics.

An All-Organic Semiconductor C3 N4 /PDINH Heterostructure with Advanced Antibacterial Photocatalytic Therapy Activity.

Antibacterial photocatalytic therapy has been reported as a promising alternative water disinfection technology for combating antibiotic-resistant bacteria. Numerous inorganic nanosystems have been developed as antibiotic replacements for bacterial infection treatment, but these are limited due to the toxicity risk of heavy metal species. Organic semiconductor photocatalytic materials have attracted great attention due to their good biocompatibility, chemically tunable electronic structure, diverse structural flexibility, suitable band gap, low cost, and the abundance of the resources they require. An all-organic composite photocatalytic nanomaterial C3 N4 /perylene-3,4,9,10-tetracarboxylic diimide (PDINH) heterostructure is created through recrystallization of PDINH on the surface of C3 N4 in situ, resulting in enhanced photocatalytic efficiency due to the formation of a basal heterostructure. The absorption spectrum of this composite structure can be extended from ultraviolet to near-infrared light (750 nm), enhancing the photocatalytic effect to produce more reactive oxygen species, which have an excellent inactivation effect on both Gram-negative and positive bacteria, while demonstrating negligible toxicity to normal tissue cells. An efficient promotion of infectious wound regeneration in mice with Staphylococcus aureus infected dermal wounds is demonstrated. This all-organic heterostructure shows great promise for use in wound disinfection.