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.

A Bi2S3-embedded gellan gum hydrogel for localized tumor photothermal/antiangiogenic therapy.

An injectable gellan gum-based nanocomposite hydrogel (Bi2S3@GG) was designed for X-ray computed tomography (CT) imaging and photothermal/antiangiogenic therapy. The linear anionic polysaccharide gellan gum (GG) was used as a stabilizer, embedded with ultra-small bismuth sulfide (Bi2S3) nanodots (∼2 nm) through a one-pot synthesis method. The as-prepared Bi2S3@GG hydrogel displays excellent capability for both photothermal therapy (PTT) (with a photothermal conversion efficiency of 44.3%) and X-ray computed tomography (with an X-ray absorption coefficient of 51.5 HU L g-1), integrated with real-time monitoring drug retention and tunable therapeutic functions. After the incorporation of sorafenib (SF), the hydrogel shows a sustained release of SF over 15 days. A tumor suppression rate of 98.2% is shown at day 22 postinjection in the mice received the combined treatments of photothermal/antiangiogenic therapy. In contrast, tumor growth and recurrence are observed in the single treatment. Our work presents a new strategy to construct a multifunctional hydrogel platform for a safe and precise antitumor therapy.

A robust hybrid nanozyme@hydrogel platform as a biomimetic cascade bioreactor for combination antitumor therapy.

The development of highly effective and minimally invasive approaches for cancer treatment is the ultimate goal. Herein, an injectable hybrid hydrogel as a biomimetic cascade bioreactor is designed for combination antitumor therapy by providing spatiotemporally-controlled and long-term delivery of therapeutic agents. This hybrid nanozyme@hydrogel (hPB@gellan) is doped with Prussian blue (PB) nanoparticles via the in situ nanoprecipitation method in the polysaccharide gellan matrix. The obtained PB nanoparticles have a small size of 10 nm and play dual roles as a photothermal agent with a photothermal conversion efficiency of 59.6% and as a nanozyme to decompose hydrogen peroxide into oxygen. By incorporating glucose oxidase (GOD) into the hybrid hydrogel, a cascade bioreactor is formed for PB-promoted glucose consumption. Owing to its shear-thinning and self-recovery properties, the hybrid hydrogel is locally administered into tumors, and shows long-term resistance against body clearance and metabolism. The in vivo antitumor results demonstrate that the tumors in the group of combined photothermal and starvation therapy (GOD/hPB@gellan + NIR) are greatly eliminated with a tumor suppression rate of 99.7% 22 days after the treatment. The outstanding antitumor performance is attributed to the main attack by NIR-triggered hyperthermia and the holding attack by GOD-mediated starvation from the catalytic bioreactor of the hybrid hydrogel. Taking into consideration the advantages of biosafety, simple synthetic approaches and facile manipulation in treatment, the hybrid hydrogel has great potential for clinical translation.

2D Monoelemental Germanene Quantum Dots: Synthesis as Robust Photothermal Agents for Photonic Cancer Nanomedicine.

As a new family member of the emerging two-dimensional (2D) monoelemental materials (Xenes), germanene has shown promising advantages over the prototypical 2D Xenes, such as black phosphorus (BP) and graphene. However, efficient manufacture of novel germanene nanostructures is still a challenge. Herein, a simple top-down approach for the liquid-exfoliation of ultra-small germanene quantum dots (GeQDs) is presented. The prepared GeQDs possess an average lateral size of about 4.5 nm and thickness of about 2.2 nm. The functionalized GeQDs were demonstrated to be robust photothermal agents (PTAs) with outstanding photothermal conversion efficacy (higher than those of graphene and BPQDs), superior stability, and excellent biocompatibility. As a proof-of-principle, 2D GeQDs-based PTAs were used in fluorescence/photoacoustic/photothermal-imaging-guided hyperpyrexia ablation of tumors. This work could expand the application of 2D germanene to the field of photonic cancer nanomedicine.

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.

Integrated Hydrogel Platform for Programmed Antitumor Therapy Based on Near Infrared-Triggered Hyperthermia and Vascular Disruption.

Complete tumor regression is a great challenge faced by single therapy of near-infrared (NIR)-triggered hyperthermia or vascular disrupting agents. An injectable nanocomposite (NC) hydrogel is rationally designed for combined anticancer therapy based on NIR-triggered hyperthermia and vascular disruption. The NC hydrogel, codelivered with Prussian blue (PB) nanoparticles and combretastatin A4 (CA4), has good shear-thinning, self-recovery, and excellent photothermal properties. Because of the remarkable tumor-site retention and sustained release of CA4 (about 10% over 12 days), the NC hydrogel has a tumor suppression rate of 99.6%. The programmed combinational therapy conveys the concept of "attack + guard", where PB-based NIR irradiation imposes intensive attack on most of cancer cells, and CA4 serves as a guard against the tumor growth by cutting off the energy supply. Moreover, the biosafety and eco-friendliness of the hydrogel platform pave the way toward clinical applications.

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.

Coordination Nanosheets of Phthalocyanine as Multifunctional Platform for Imaging-Guided Synergistic Therapy of Cancer.

"All-in-one" nanodrugs integrating various functionalities into one nanosystem are highly desired for cancer treatment. Coordination nanosheets as one type of two dimensional (2D) nanomaterials offer great opportunities, but there is lack of enough candidates. Here, a new kind of coordination nanosheets based on phthalocyanine are constructed. Manganese phthalocyanine (MnPc) tetracarboxylic acid is employed as photoactive ligand to form MnPc nanosheets; meanwhile, hyaluronic acid (HA) is coated on their surface. The obtained MnPc@HA nanosheets exhibit superior near-infrared (NIR) photothermal effect with photothermal conversion efficiency of 72.3%, much higher than those of the previously reported photothermal agents. Due to their 2D nanostructures, MnPc@HA nanosheets possess superhigh drug-loading capacity for chemotherapy drug curcumin. With HA as a targeting group, the nanosheets selectively accumulated in CD44 overexpressed tumors, followed by drug release under the control of NIR light. Moreover, MnPc@HA nanosheets with intrinsic paramagnetism can serve as T1 contrast agent for magnetic resonance imaging. The synergistic effect of phototherapy and chemotherapy endows curcumin-loaded MnPc@HA nanosheets with superior tumor-eradicating efficacy. Besides, MnPc@HA nanosheets are biocompatible and safe for biomedical applications. This work provides novel insight for developing new multifunctional platforms based on 2D coordination nanosheets to synergistically combat cancer.

Fabrication of injectable CuS nanocomposite hydrogels based on UCST-type polysaccharides for NIR-triggered chemo-photothermal therapy.

Injectable nanocomposite hydrogels containing small copper sulfide nanoparticles (6-8 nm) with a 54.6% photothermal conversion efficiency have been facilely prepared by applying an upper critical solution temperature (UCST)-type biopolymer gellan. This minimally invasive formulation ablates cancer completely in vivo after NIR-triggered chemo-photothermal therapy.

Dual Roles of Protein as a Template and a Sulfur Provider: A General Approach to Metal Sulfides for Efficient Photothermal Therapy of Cancer.

Fabrication of clinically translatable nanoparticles (NPs) as photothermal therapy (PTT) agents against cancer is becoming increasingly desirable, but still challenging, especially in facile and controllable synthesis of biocompatible NPs with high photothermal efficiency. A new strategy which uses protein as both a template and a sulfur provider is proposed for facile, cost-effective, and large-scale construction of biocompatible metal sulfide NPs with controlled structure and high photothermal efficiency. Upon mixing proteins and metal ions under alkaline conditions, the metal ions can be rapidly coordinated via a biuret-reaction like process. In the presence of alkali, the inert disulfide bonds of S-rich proteins can be activated to react with metal ions and generate metal sulfide NPs under gentle conditions. As a template, the protein can confine and regulate the nucleation and growth of the metal sulfide NPs within the protein formed cavities. Thus, the obtained metal sulfides such as Ag2 S, Bi2 S3 , CdS, and CuS NPs are all with small size and coated with proteins, affording them biocompatible surfaces. As a model material, CuS NPs are evaluated as a PTT agent for cancer treatment. They exhibit high photothermal efficiency, high stability, water solubility, and good biocompatibility, making them an excellent PTT agent against tumors. This work paves a new avenue toward the synthesis of structure-controlled and biocompatible metal sulfide NPs, which can find wide applications in biomedical fields.

Black Phosphorus Nanosheets as a Neuroprotective Nanomedicine for Neurodegenerative Disorder Therapy.

Transition-metal dyshomeostasis is recognized as a critical pathogenic factor at the onset and progression of neurodegenerative disorder (ND). Excess transition-metal ions such as Cu2+ can catalyze the generation of cytotoxic reactive oxygen species and thereafter induce neuronal cell apoptosis. Exploring new chelating agents, which are not only capable of capturing excess redox-active metal, but can also cross the blood-brain barrier (BBB), are highly desired for ND therapy. Herein, it is demonstrated that 2D black phosphorus (BP) nanosheets can capture Cu2+ efficiently and selectively to protect neuronal cells from Cu2+ -induced neurotoxicity. Moreover, both in vitro and in vivo studies show that the BBB permeability of BP nanosheets is significantly improved under near-infrared laser irradiation due to their strong photothermal effect, which overcomes the drawback of conventional chelating agents. Furthermore, the excellent biocompatibility and stability guarantee the biosafety of BP in future clinical applications. Therefore, these features make BP nanosheets have the great potential to work as an efficient neuroprotective nanodrug for ND therapy.

Black Phosphorus Nanosheet-Based Drug Delivery System for Synergistic Photodynamic/Photothermal/Chemotherapy of Cancer.

A black phosphorus (BP)-based drug delivery system for synergistic photodynamic/photothermal/chemotherapy of cancer is constructed. As a 2D nanosheet, BP shows super high drug loading capacity and pH-/photoresponsive drug release. The intrinsic photothermal and photodynamic effects of BP enhance the antitumor activities. The synergistic photodynamic/photothermal/chemotherapy makes BP-based drug delivery system a multifunctional nanomedicine platform.

Fabrication of biopolymeric complex coacervation core micelles for efficient tea polyphenol delivery via a green process.

Nanoencapsulation is a promising method to improve the bioavailability of tea polyphenol (TPP). In this work, we adopted a green process to develop a new kind of complex coacervation core micelles (C3Ms) based on biopolymers for efficient tea polyphenol delivery. First, gelatin-dextran conjugate was synthesized using Maillard reaction. Then the C3Ms were produced by mixing gelatin-dextran conjugate with TPP. Variable factors on the self-assembly of the C3Ms were investigated. Under optimal conditions, the obtained C3Ms are of nanosize (average 86 nm in diameter) with narrow distribution. The formation of the C3Ms is attributed to hydrophobic interaction and hydrogen bonding instead of electrostatic interaction. Transmission electron microscope (TEM) and scanning electron microscope (SEM) results showed that C3Ms have a spherical shape with core-shell structure. ζ-Potential measurement suggested that the core is composed of gelatin with TPP, whereas the shell is composed of dextran segments. The encapsulation efficiency of the C3Ms is pH-independent, but the loading capacity is controllable and as high as 360 wt % (weight/weight of protein). In addition, the C3Ms show sustained release of TPP in vitro. MTT assay revealed that the C3Ms have comparable or even stronger cytotoxicity against MCF-7 cells than free TPP.

Synthesis and evaluation of ferrocenoyl pentapeptide (Fc-KLVFF) as an inhibitor of Alzheimer's Aß1-42 fibril formation in vitro.

Aggregation and fibril formation of ß-amyloid peptides (Aß) is the key event in the pathogenesis of Alzheimer's disease. Many efforts have been made on the development of effective inhibitors to prevent Aß fibril formation or disassemble the preformed Aß fibrils. Peptide inhibitors with sequences homologous to the hydrophobic segments of Aß can alter the aggregation pathway of Aß, together with decrease of the cell toxicity. In this study, the conjugate of ferrocenoyl (Fc) with pentapeptide KLVFF (Fc-KLVFF), was synthesized by HBTU/HOBt protocol in solution. The inhibitory effect of Fc-KLVFF on Aß(1-42) fibril formation was evaluated by thioflavin T fluorescence assay, and confirmed by atomic force microscopy (AFM) and transmission electron microscopy (TEM) analyses. Fc-KLVFF shows high inhibitory effect towards the fibril formation of Aß(1-42). Additionally, the attachment of ferrocenoyl moiety onto peptides allows us to investigate the interaction between the inhibitor and Aß(1-42) in real-time by electrochemical method. As expected, tethering of ferrocenoyl moiety onto pentapeptide shows improved lipophilicity and significant resistance towards proteolytic degradation compared to its parent peptide.