In Situ Synthesis of Natural Antioxidase Mimics for Catalytic Anti-Inflammatory Treatments: Rheumatoid Arthritis as an Example.

Mimicking the coordination geometry of the active metal sites of natural enzymes is an efficient strategy in designing therapeutic chemicals with enzymelike in vivo reaction thermodynamics and kinetics. In this study, this chemical concept has been applied for the in situ synthesis of natural antioxidase mimics for catalytic anti-inflammatory treatment by using rheumatoid arthritis, a common and hardly curable immune-mediated diseases, as an example. Briefly, a composite nanomedicine has been first constructed by loading cationic porphyrin ligands into a manganese-engineered mesoporous silica nanocarrier, which can respond to a mildly acidic environment to concurrently release manganous ions and porphyrin ligands, enabling their subsequent coordination and synthesis of manganese porphyrin with a coordination environment of an active Mn site similar to those of the metal sites in natural superoxide dismutase (SOD) and catalase. Due to the strong metal-ligand exchange coupling enabled by the N-ethylpyridinium-2-yl groups tetrasubstituted in the meso positions of N4-macroheterocycles, such a manganese porphyrin presents the SOD-like activity of disproportionating superoxide anions via outer-sphere proton-coupled one-electron transfer (diaquamanganese(III)/monoaquamanganese(II) cycling), as well as the catalase-like activity of disproportionating hydrogen peroxide via inner-sphere proton-coupled two-electron transfer (diaquamanganese(III)/dioxomanganese(V) cycling). Cellular experiments demonstrated the high antioxidative efficacy of the composite nanomedicine in M1 macrophages by promoting their polarization shift to the anti-inflammatory M2 phenotype. Equally importantly, the silicon-containing oligomers released from the manganese silicate nanocarrier can act as heterogeneous nucleation centers of hydroxyapatite for facilitating biomineralization by bone mesenchymal stem cells. Finally, an in vivo adjuvant-induced arthritis animal model further reveals the high efficacy of the nanomedicine in treating rheumatoid arthritis.

Photosynthetic Cyanobacteria-Hybridized Black Phosphorus Nanosheets for Enhanced Tumor Photodynamic Therapy.

Photodynamic therapy (PDT) has attracted tremendous attention due to its advantages such as high safety and effectiveness compared to traditional radiotherapy and chemotherapy. However, the intratumoral hypoxic microenvironment will inevitably compromise the PDT effect of the highly oxygen-dependent type II photosensitizers, implicating the urgent demand for continuous intratumoral oxygenation. Herein, biocompatible photosynthetic cyanobacteria have been modified with inorganic two-dimensional black phosphorus nanosheets (BPNSs) to be a novel bioreactor termed as Cyan@BPNSs. Upon 660 nm laser irradiation, the photosynthetic cyanobacteria generate oxygen continuously in situ through photosynthesis, followed by the photosensitization of BPNSs for activating oxygen into singlet oxygen (1 O2 ), resulting in a large amount of 1 O2 accumulation at the tumor site and the consequent strong tumor cell killing effect both in vitro and in vivo. This work provides an attractive strategy for efficient and biocompatible PDT, meanwhile extends the scope of microbiotic nanomedicine by hybridizing microorganisms with inorganic nanophotosensitizer.

Lysine demethylase KDM3A regulates nanophotonic hyperthermia resistance generated by 2D silicene in breast cancer.

Breast cancer (BC) is the most common malignant disease affecting women's health worldwide. The benefits from conventional therapeutic modalities are severely limited. An increasing number of promising photothermal materials have been recently developed and introduced into the therapeutic regimens of BC, but the underlying biological mechanism remains unclear. Silicon-based materials have enjoyed many popularities in the biomedical field owing to their desirable biocompatibility, biodegradability and versatility. Herein, we introduced two dimensional (2D) silicene nanosheets (SNSs) into the BC treatment and achieved profound photothermal-ablation efficacy. Importantly, this work reveals the underlying biological mechanism and regulation factors of photonic hyperthermia in BC. The RNA sequencing and immunoblot demonstrated that photothermia enhanced apoptosis in BC by activating caspase 3 and caspase 7. Importantly, knockdown of lysine demethylase KDM3A sensitized BC to photothermia epigenetically. It has been revealed that KDM3A could erase p53K372me1 and suppress the anti-cancer functions of p53, leading to the downregulation of pro-apoptotic proteins-PUMA and NOXA verified by Co-IP and ChIP-qPCR assays. Therefore, our results not only import near infrared light (NIR) induced photothermal ablation generated by SNSs-BSA into the BC treatment, but also clarify the underlying mechanism and regulation factors for further photothermal performance optimization and clinical translation.

Combined Magnetic Hyperthermia and Immune Therapy for Primary and Metastatic Tumor Treatments.

Cancer immunotherapy shows promising potential in future cancer treatment but unfortunately is clinically unsatisfactory due to the low therapeutic efficacy and the possible severe immunotoxicity. Here we show a combined magnetic hyperthermia therapy (MHT) and checkpoint blockade immunotherapy for both primary tumor ablation and mimetic metastatic tumor inhibition. Monodispersed, high-performance superparamagnetic CoFe2O4@MnFe2O4 nanoparticles were synthesized and used for effective MHT-induced thermal ablation of primary tumors. Simultaneously, numerous tumor-associated antigens were produced to promote the maturation and activation of dendritic cells (DCs) and cytotoxic T cells for effective immunotherapy of distant mimetic metastatic tumors in a tumor-bearing mice model. The combined MHT and checkpoint blockade immunotherapy demonstrate the great potentials in the fight against both primary and metastatic tumors.

Clearable Theranostic Platform with a pH-Independent Chemodynamic Therapy Enhancement Strategy for Synergetic Photothermal Tumor Therapy.

Chemodynamic therapy (CDT) is an emerging field, which utilizes intratumoral iron-mediated Fenton chemistry for cancer therapy. However, the slightly acidic tumor environment is improper for the classical Fenton reaction, which is generally energetic in a narrow pH range (e.g., pH = 3-4). Herein, a kind of ultrasmall bovine serum albumin (BSA)-modified chalcopyrite nanoparticles (BSA-CuFeS2 NPs) was synthesized via a facile aqueous biomineralization strategy, which shows high dispersity and biocompatibility. Interestingly, the obtained BSA-CuFeS2 shows a pH-independent Fenton-like reaction, which could exert Fenton-like activity to efficiently generate •OH under a weak acidic tumor environment. Combined with the extraordinarily high photothermal conversion (38.8%), BSA-CuFeS2 shows the synergistic function of high photothermal therapy (PTT) and enhanced CDT, that is, PTT/CDT. Importantly, such ultrasmall BSA-CuFeS2 NPs measuring around 4.9 nm can be quickly cleared out of the body through kidneys and liver, thus effectively avoiding long-term toxicity and systemic toxicity. Moreover, BSA-CuFeS2 NPs can act as an efficient T2-weighted magnetic resonance imaging (MRI) contrast agent to guide tumor ablation in vivo. This work offers a universal approach to boost production •OH by a pH-independent Fenton-like reaction strategy and achieves MRI-guided synergistic enhanced photothermal-CDT for highly efficient tumor treatment.

Ultrasmall Cu2-xS nanodots as photothermal-enhanced Fenton nanocatalysts for synergistic tumor therapy at NIR-II biowindow.

Reactive oxygen species (ROS)-mediated nanocatalytic therapy, as conducted by the tumor microenvironment to generate toxic hydroxyl (OH) radicals with the assistant of Fenton nanocatalysts, exhibits high tumor-therapeutic promise due to its high therapeutic selectivity and desirable therapeutic outcome. The mostly explored Fe-based Fenton nanocatalysts-enabled nanocatalytic cancer therapy substantially suffers from lowed pH condition and the corresponding therapeutic effect is still far from satisfactory for further clinic application. In this work, we report, for the first time, that copper (Cu)-based nanocatalysts have the intrinsic capability to catalyze hydrogen peroxide (H2O2) into hydroxyl radicals in a wide range pH condition with the comparable and even better performance as compared to mostly explored Fe-based nanocatalysts. Especially, ultrasmall (≤5 nm) PEGylated Cu2-xS nanodots (Cu2-xS-PEG) were fabricated to serve as the novel Fenton nanocatalysts for nanocatalytic tumor therapy. Importantly, taking the unique advantage of high near infrared (NIR) light absorbance at NIR-II biowindow (1000-1350 nm), light-activated photonic theranostic modality, i.e. photoacoustic imaging and photothermal therapy at both NIR-II biowindows was introduced, which could efficiently delineate/monitor the tumor regions and synergistically enhance Fenton-mediated therapeutic efficacy by photonic hyperthermia, respectively. Both systematic in vitro and in vivo experiments have demonstrated the high therapeutic efficacy of Cu2-xS-enabled synergistic photothermal hyperthermia-enhanced nanocatalytic therapy. This work not only provides a nanoparticle-augmented synergistic cancer-therapeutic modality, but also enriches the totally new nanocatalyst types for catalytic Fenton reaction-based nanocatalytic tumor therapy.

2D-Black-Phosphorus-Reinforced 3D-Printed Scaffolds:A Stepwise Countermeasure for Osteosarcoma.

With the ever-deeper understanding of nano-bio interactions and the development of fabrication methodologies of nanomaterials, various therapeutic platforms based on nanomaterials have been developed for next-generation oncological applications, such as osteosarcoma therapy. In this work, a black phosphorus (BP) reinforced 3D-printed scaffold is designed and prepared to provide a feasible countermeasure for the efficient localized treatment of osteosarcoma. The in situ phosphorus-driven, calcium-extracted biomineralization of the intra-scaffold BP nanosheets enables both photothermal ablation of osteosarcoma and the subsequent material-guided bone regeneration in physiological microenvironment, and in the meantime endows the scaffolds with unique physicochemical properties favoring the whole stepwise therapeutic process. Additionally, a corrugated structure analogous to Haversian canals is found on newborn cranial bone tissue of Sprague-Dawley rats, which may provide much inspiration for the future research of bone-tissue engineering.

Theranostic 2D ultrathin MnO2 nanosheets with fast responsibility to endogenous tumor microenvironment and exogenous NIR irradiation.

The fabrication of functional nanoparticles with unique ultra-sensitivity to endogenous tumor microenvironment (TME) is of great significance for their improved theranostic performance and easy excretion out of the body, which has not been realized among diverse nano-sized photothermal agents for photothermal therapy (PTT) of tumor. In this work, we report on the synthesis of 2D ultrathin MnO2 nanosheets for highly efficient PTT against tumor with ultra-sensitivity to endogenous TME. These ultrathin 2D MnO2 nanosheets show the intriguing characteristic of disintegration and releasing of Mn2+ in response to the mild acidic condition and elevated reducing microenvironment of TME, which has successfully realized the pH- and reducing-responsive T1-weighted magnetic resonance imaging of tumor. Importantly, the high PTT efficiency of 2D MnO2 nanosheets responsive to exogenous NIR irradiation has been systematically demonstrated both in vitro and in vivo for suppressing the tumor growth. This first report on the exploring of TME-sensitive photothermal agents with concurrent diagnostic and therapeutic (theranostic) functions significantly broadens the biomedical application of 2D functional biomaterials, which also promotes the further potential clinical translations of nano-sized photothermal agents.

A Facile One-Pot Synthesis of a Two-Dimensional MoS2 /Bi2S3 Composite Theranostic Nanosystem for Multi-Modality Tumor Imaging and Therapy.

2D PEG-ylated MoS2/Bi2 S3 composite nanosheets are successfully constructed by introducing bismuth ions to react with the two extra S atoms in a (NH4)2 MoS4 molecule precursor for solvothermal synthesis of MoS2. The MBP nanosheets can serve as a promising platform for computed tomography and photoacoustic-imaging-guided tumor diagnosis, as well as combined tumor photothermal therapy and sensitized radiotherapy.