Iridium oxide nanoparticles mediated enhanced photodynamic therapy combined with photothermal therapy in the treatment of breast cancer.

Photodynamic therapy (PDT) of tumor has achieved good results, but the treatment efficiency is not high due to the lack of effective photosensitizers and tumor hypoxia. In this study, iridium dioxide nanoparticles (IrO2 NPs) with excellent photothermal/photodynamic effects and catalase like activity were synthesized by a simple method. The combination of glucose oxidase (GOx) and IrO2 NPs is formed by hyaluronic acid (HA), which have the activities of glucose oxidase and catalase, can target tumor sites and form in situ amplifiers in tumor microenvironment (IrO2-GOx@HA NPs). Firstly, GOx convert the high levels of glucose in the tumor to hydrogen peroxide (H2O2), and then IrO2 NPs convert H2O2 to oxygen (O2), which can enhance the type II of PDT. IrO2 NPs also can be used as a thermosensitive agent for photothermal therapy (PTT). In cancer cells, IrO2-GOx@HA NPs-mediated amplifier enhances the effect of type II of PDT, aggravating the apoptosis of breast cancer (4T1) cells and cooperating with its own PTT to further improve the overall treatment effect. Under simulated hypoxic conditions of tumor tissue, it was found that IrO2-GOx@HA NPs treatment can effectively relieve hypoxia inside tumor tissue. In addition, the results in vivo further proved that, IrO2-GOx@HA NPs can enhance the role of II PDT and cooperate with PTT to treat breast cancer effectively. The results highlight the prospect of IrO2-GOx@HA NPs in controlling and regulating tumor hypoxia to overcome the limitations of current cancer therapy.

In situ hydrogen nanogenerator for bimodal imaging guided synergistic photothermal/hydrogen therapies.

Multifunctional nanoagents integrating multiple therapeutic and imaging functions hold promise in the field of non-invasive and precise tumor therapies. However, the complex preparation process and uncertain drug metabolism of nanoagents loaded with various therapeutic agents or imaging agents greatly hinder its clinical applications. Developing simple and effective nanoagents that integrate multiple therapeutic and imaging functions remain a huge challenge. Therefore, a novel strategy based on in situ hydrogen release is proposed in this work: aminoborane (AB) was loaded onto mesoporous polydopamine nanoparticles (MPDA NPs) as a prodrug for hydrogen production, and then, PEG was modified on the surface of nanoparticles (represented as AB@MPDA-PEG). MPDA NPs not only act as photothermal agents (PTA) with high photothermal conversion efficiency (808 nm, η = 38.72%) but also as the carriers of AB accumulated in the tumor through enhanced permeability and retention (EPR) effect. H2 gas generated by AB in the weak acid conditions of the tumor microenvironment (TME) not only was used to treat tumors via a combination of hydrogen and photothermal therapies but also serves as a US and CT contrast agent, providing accurate guidance for tumor treatment. Finally, in vivo and in vitro investigation suggest that the designed multifunctional nanosystem not only showed excellent properties such as high hydrogen-loading capacity, long-lasting sustained hydrogen release ability and excellent biocompatibility but also achieve selective PTT/hydrogen therapies and US/CT bimodal imaging functions, which can effectively guide antitumor therapies. The proposed hydrogen gas-based strategy for combination therapies and bimodal imaging integration holds promise as an efficient and safe tumor treatment for future clinical translation.

Selenium nanoparticles with various morphology for antiangiogenesis through bFGF-mediated P13K/AKT signaling pathways.

Selenium nanoparticles (Se NPs) have potential antitumor activity and immune properties. However, the mechanism between its antitumor activity and nanoparticle morphology has not been evaluated. Therefore, a simple method was used to synthesize three special shapes of Se NPs, which are fusiform, flower and spherical. Compared with fusiform selenium nanoparticles (Se NPs (S)) and flower-shaped selenium nanoparticles (Se NPs (F)), spherical selenium nanoparticles (Se NPs (B)) have better cell absorption effect and stronger antitumor activity. HRTEM showed that Se NPs (B) entered the nucleus through endocytosis and inhibited tumor angiogenesis by targeting basic fibroblast growth factor (bFGF). Se NPs (B) can competitively inhibit the binding of bFGF to fibroblast growth factor receptor through direct binding to bFGF, down-regulate the expression of bFGF in human umbilical vein endothelial cells (HUVEC), and significantly reduce the MAPK/Erk and P13K/AKT pathways activation of signaling molecules to regulate HUVEC cell migration and angiogenesis. These findings indicate that Se NPs have a special role in antitumor angiogenesis. This research provides useful information for the development of new strategies for effective drug delivery nanocarriers and therapeutic systems.

In situ fabrication of MS@MnO2 hybrid as nanozymes for enhancing ROS-mediated breast cancer therapy.

The reactive oxygen species (ROS)-mediated anti-cancer therapy that shows the advantages of tumor specificity, high curative effect, and less toxic side-effects has powerful potential for cancer treatment. However, hypoxia in the tumor microenvironment (TME) and low penetrability of photosensitizers further limit their clinical application. Here, we present a composite core-shell-structured nanozyme (MS-ICG@MnO2@PEG) that consists of a mesoporous silica nanoparticle (MS) core and a MnO2 shell loaded with the photosensitizer indocyanine green (ICG) and then coated with PEG as the photodynamic/chemodynamic therapeutic agent for the ROS-mediated cancer treatment. On the one hand, MS-ICG@MnO2@PEG catalyzes H2O2 to produce O2 for enhanced photodynamic therapy (PDT), and on the other hand, it consumes GSH to trigger a Fenton-like reaction that generates *OH, thus enhancing the chemodynamic therapy (CDT). At the cellular level, MS-ICG@MnO2@PEG nanozymes exhibit good biocompatibility and induce the production of ROS in 4T1 tumor cells. It disrupts the redox balance in tumor cells affecting the mitochondrial function, and specifically kills the tumor cells. In vivo, the MS-ICG@MnO2@PEG nanozymes selectively accumulate at tumor sites and inhibit tumor growth and metastasis in 4T1 tumor-bearing mice. Accordingly, this study shows that the core-shell nanozymes can serve as an effective platform for the ROS-mediated breast cancer treatment by enhancing the combination of PDT and CDT.

Ru@CeO2 yolk shell nanozymes: Oxygen supply in situ enhanced dual chemotherapy combined with photothermal therapy for orthotopic/subcutaneous colorectal cancer.

Hypoxia is an important factor in forming multidrug resistance, recurrence and metastasis in solid tumors. Nanozymes respond to tumor microenvironment for tumor-specific treatment is a new and effective strategy. In this study, one-pot method was used to synthesize hollow Ru@CeO2 yolk shell nanozymes (Ru@CeO2 YSNs), which possess excellent light-to-heat conversion efficiency and catalytic performance. Antitumor drug ruthenium complex (RBT) and resveratrol (Res) were dual-loaded in Ru@CeO2 YSNs, and a double outer layer structure using polyethylene glycol was constructed to form dual-drug delivery system (Ru@CeO2-RBT/Res-DPEG) that was released on demand. The double outer layer structure increased the biocompatibility of Ru@CeO2 YSNs and effectively prolong the circulation time in blood. Ru@CeO2-RBT/Res-DPEG catalyzes endogenous H2O2 to produce oxygen, which achieve in situ oxygen supply and enhanced dual-chemotherapy and photothermal therapy (PTT) for colorectal cancer. In vitro studies found that Ru@CeO2-RBT/Res-DPEG has good tumor penetration depth and antitumor effect. In addition, Ru@CeO2-RBT/Res-DPEG can alleviate tumor hypoxia, and inhibit metastasis and recurrence of orthotopic and subcutaneous colorectal cancer. Accordingly, the study shows that yolk shell nanozymes can be used as an efficient synergistic system for dual-chemotherapy and PTT to kill tumor and inhibit orthotopic colorectal cancer metastasis and recurrence.

Responsive functionalized MoSe2 nanosystem for highly efficient synergistic therapy of breast cancer.

The photothermal/photodynamic synergistic therapy is a promising tumor treatment, but developing nanosystems that achieve synchronous photothermal/photodynamic functions is still quite challenging. Here, we use a simple method to synthesize molybdenum selenide nanoparticles (MoSe2 NPs) with a photothermal effect as a carrier, and load a photosensitizer ICG to form a nanosystem (MoSe2@ICG-PDA-HA)with dual photothermal/photodynamic functions under near-infrared irradiation. In addition, the surface modification of the nanosystem with acid-responsive release polydopamine (PDA) and tumor-targeted hyaluronic acid (HA) enhanced the stability of the photosensitizer ICG and the accumulation of ICG at tumor sites. The multicellular sphere assay simulated solid tumors and demonstrated that MoSe2@ICG-PDA-HA could significantly inhibit the 4T1 cell growth. The anti-tumor experiments in tumor-bearing mice showed that MoSe2@ICG-PDA-HA not only significantly inhibited the growth of 4T1 subcutaneous tumors, but also inhibited their metastasis. This study presented a nanosystem that could improve the photostability of optical materials and enhance the photothermal/photodynamic synergy effect, providing a new idea for finding a way to effectively treat breast cancer.

Intelligently thermoresponsive flower-like hollow nano-ruthenium system for sustained release of nerve growth factor to inhibit hyperphosphorylation of tau and neuronal damage for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) seriously affects human health and life and lacks effective treatments. The lessons of many clinical trial failures suggest that targeting amyloid beta to treat AD is difficult, and finding new targets is an important direction for AD drug research. The neurofibrillary tangles formed by hyperphosphorylation of tau protein induce the production of cytotoxic reactive oxygen species (ROS) and cause neuronal apoptosis. Therefore, inhibition of hyperphosphorylation of tau protein and reduction of neuronal damage have become promising methods for the treatment of AD. We herein designed a novel nanocomposite with high stability and good biocompatibility by using flower-shaped hollow nano-ruthenium (Ru NPs) as a carrier, loading nerve growth factor (NGF) and sealing with phase change material (PCM). Due to its excellent photothermal effect, under the near-infrared (NIR) irradiation, the nanocomposite could effectively penetrate the blood-brain barrier (BBB) and respond to phase changes in the lesion area, releasing NGF, which inhibited tau hyperphosphorylation, reduced oxidative stress, and more importantly restored nerve damage and maintained neuronal morphology, thereby significantly improving learning and memory in AD mice. Thus, the experimental results indicate that multifunctional nanocomposites may be a promising drug in the treatment of AD.

Iridium/ruthenium nanozyme reactors with cascade catalytic ability for synergistic oxidation therapy and starvation therapy in the treatment of breast cancer.

The application of nanozymes to specifically treat tumors in the tumor microenvironment (TME) would be a novel and effective strategy. Here, ultra-small IrRu alloy nanoparticles (IrRu NPs) with dual enzyme activities were synthesized by a simple method. PEG surface modification was carried out to improve the biocompatibility of nanoparticles. Meanwhile, the natural enzyme glucose oxidase (GOx) was loaded to synthesize a multi-enzyme nanoreactor (IrRu-GOx@PEG NPs) that could undergo cascade catalytic reaction. In the first catalytic stage, GOx in IrRu-GOx@PEG NPs degraded tumor tissue-sensitive glucose to hydrogen peroxide (H2O2), which cut off the nutrient source of the tumor and inhibited tumor growth by starvation therapy. In the second catalytic stage, IrRu NPs in IrRu-GOx@PEG NPs catalyzed the upstream endogenous H2O2 to highly toxic singlet oxygen 1O2 and O2. Among them, 1O2 could directly induce apoptosis of cancer cells by the oxidative therapy, and O2 could resolve the problem of hypoxia that easily led to the termination of the starvation therapy response in tumor microenvironment, thereby making the cycle of starvation therapy-related reactions continue to occur. It also inhibited the metastasis of tumors caused by hypoxia. In vitro catalytic activity studies showed that IrRu-GOx@PEG NPs had good and stable catalytic activity and could effectively induce apoptosis of 4T1 cancer cells. In addition, in vivo results further demonstrated that IrRu-GOx@PEG NPs could effectively treat breast cancer in combination with starvation therapy and oxidative therapy. This treatment strategy is expected to be used in the treatment of other cancers, bringing new treatment strategies for cancer treatment.

Photothermal-Chemotherapy Integrated Nanoparticles with Tumor Microenvironment Response Enhanced the Induction of Immunogenic Cell Death for Colorectal Cancer Efficient Treatment.

Inducing immunogenic cell death (ICD) that enhances the immunogenicity of dead cancer cells is a new strategy for tumor immunotherapy, but efficiently triggering ICD is the biggest obstacle to achieving this strategy, especially for distant and deep-seated tumors. Here, a new therapeutic system (Pd-Dox@TGMs NPs) that can effectively trigger ICD by combining chemotherapy and photothermal therapy was designed. The nanosystem was fabricated by integrating doxorubicin (Dox) and a photothermal reagent palladium nanoparticles (Pd NPs) into amphiphile triglycerol monostearates (TGMs), which showed specific accumulation, deep penetration, and activation in response to the tumoral enzymatic microenvironment. It was proved that codelivery of Dox and Pd NPs not only effectively killed CT26 cells through chemotherapy and photothermal therapy but also promoted the release of dangerous signaling molecules, such as high mobility group box 1, calreticulin, and adenosine triphosphate, improving the immunogenicity of dead tumor cells. The effective ICD induction mediated by Pd-Dox@TGMs NPs boosted the PD-L1 checkpoint blockade effect, which efficiently improved the infiltration of toxic T lymphocytes at the tumor site and showed excellent tumor treatment effects to both primary and abscopal tumors. Therefore, this work provides a simple and effective immunotherapeutic strategy by combining chemical-photothermal therapy to enhance immune response.

Inflammation-responsive functional Ru nanoparticles combining a tumor-associated macrophage repolarization strategy with phototherapy for colorectal cancer therapy.

Due to the complexity and heterogeneity of solid tumors, traditional clinical treatments often only achieve limited therapeutic effects. Tumor-associated macrophages (TAMs) play a key role in the development of solid tumors, and the elimination of solid tumors based on the tumor microenvironment has proven to be an effective therapeutic strategy. Here, we successfully developed Ru-based nanoparticles, Ru@ICG-BLZ NPs, with inflammation-responsive release ability, which could repolarize TAMs into M1 macrophages (with an antitumor role) and further produce hyperthermia and ROS to eliminate cancer cells. In vitro experiments showed that Ru@ICG-BLZ NPs had superior drug (ICG and BLZ-945) loading capacity and sensitive inflammation-responsive drug release behavior, which enhanced CT26 cell uptake and penetration ability. Furthermore, in vivo experiments showed that Ru@ICG-BLZ NPs could effectively up-regulate the expression of M1 markers (iNOS, and IL-12) and exert phototherapy to ablate solid tumor, without causing obvious damage to the surrounding tissues of the tumor. The lower toxicity and excellent antitumor ability of Ru@ICG-BLZ NPs could provide new ideas for the clinical transformation of nanomedicine.

A core-shell structure QRu-PLGA-RES-DS NP nanocomposite with photothermal response-induced M2 macrophage polarization for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a degenerative joint disease caused by autoimmunity; for the effective treatment of RA while avoiding the side effects of conventional drugs, we have proposed a new therapeutic strategy to eliminate the inflammatory response in RA by regulating the immune system that promotes the transformation of M1-type macrophages to M2-type macrophages. Herein, we designed and synthesized a core-shell nanocomposite (QRu-PLGA-RES-DS NPs), which showed an effective therapeutic effect on RA by accurately inducing the polarization of M2 macrophages. In this system, the quadrilateral ruthenium nanoparticles (QRuNPs) with a photothermal effect were utilized as a core and the thermosensitive molecular poly (lactic-co-glycolic acid) (PLGA) modified with the targeted molecule dextran sulfate (DS) was employed as a shell. Then, the nanocarrier QRu-PLGA-DS NPs effectively improved the water solubility and targeting of resveratrol (RES) through self-assembly. Therefore, the QRu-PLGA-RES-DS NPs significantly enhanced the ability of RES to reverse the M1 type macrophages to the M2 type macrophages through an accurate release. In vivo experiments further demonstrated that the QRu-PLGA-RES-DS NPs could effectively accumulate in the lesion area with an exogenous stimulus, and this significantly enhanced the transformation of the M2 type macrophages and decreased the recruitment of the M1 type macrophages. Furthermore, the QRu-PLGA-RES-DS NPs effectively treated RA by eliminating the inflammatory response; in addition, photoacoustic imaging (PA) of the QRu NPs provided image guidance for the distribution and analysis of nanomedicine in inflammatory tissues. Hence, this therapeutic strategy promotes the biological applications of Ru-based nanoparticles in disease treatment.

Enzyme-Responsive Mesoporous Ruthenium for Combined Chemo-Photothermal Therapy of Drug-Resistant Bacteria.

The rapid mutation of drug-resistant bacteria and the serious lag of development of new antibiotics necessitate research on novel antibacterial agents. Nanomaterials with unique size effect and antibacterial mechanism could serve as an alternative for antibiotics, since they showed low possibility to develop drug-resistant bacteria. Here, an enzyme-responsive nanosystem, AA@Ru@HA-MoS2, with a synergistic chemo-photothermal therapy function is proposed to treat bacterial infections. Mesoporous ruthenium nanoparticles (Ru NPs) were used as nanocarriers, loading prodrug ascorbic acid (AA) and encapsulated by hyaluronic acid (HA). Then, molybdenum disulfide (MoS2) precoated with ciprofloxacin was used as a catalyst with targeting effect binding to the outer surface. When the nanosystem gathered at the infection site, Hyal secreted by bacteria could degrade the HA capping and trigger the release of AA and then generated hydroxyl radicals (•OH) in situ by the catalysis of MoS2. In addition, taking advantage of the good photothermal property of Ru NPs, combined chemo-photothermal antibacterial therapy could be achieved. The nanosystem exhibited potent bactericidal activity against drug-resistant Gram-positive and Gram-negative bacteria. Furthermore, it could break down the biofilm, inhibit the contained bacteria, and prevent the formation of a new biofilm. The in vivo bacterium-infected model also proved accelerated wound healing. The study showed a high potential of AA@Ru@HA-MoS2 as a novel enzyme-responsive nanosystem for combating drug-resistant bacterial infection.

Quercetin-modified gold-palladium nanoparticles as a potential autophagy inducer for the treatment of Alzheimer's disease.

At present, autophagic dysfunction has been considered to be involved in the pathogenesis of Alzheimer's disease (AD). Thus, the activation of autophagy provides a potential means of eliminating the intracellular amyloid-ß (Aß) and slows down the neurotoxicity induced by Aß. Here, we synthesize a Quercetin (Qu) modified polysorbate 80 (P-80)-coated AuPd core-shell structure. Our results indicate that Concave cubic Qu@P-80@AuPd can activate autophagy of SH-SY5Y cells, promote the fusion of autophagosomes and lysosomes, accelerate the clearance of Aß, and protect SH-SY5Y cells from Aß-induced cytotoxicity damage. Furthermore, Concave cubic Qu@P-80@AuPd also has good biocompatibility and high blood-brain barrier (BBB) permeability. Therefore, we anticipate that Concave cubic Qu@P-80@AuPd will be used as a potential autophagy inducer to treat AD.