Bidirectional anisotropic palladium nanozymes reprogram macrophages to enhance collaborative chemodynamic therapy of colorectal cancer.

In the complex tumor microenvironment (TME), tumor-associated macrophages (TAMs) play an important role in immunosuppression and tumor growth; hence, tumor cells are no longer the only target during tumor treatment. However, how to simultaneously target both tumor cells and TAMs to effectively eliminate the tumor remains a challenge. Herein, based on the specific receptors for cancer cells and TAMs, we prepared bidirectional anisotropic palladium nanoclusters (Pd-HA+Pd-M@R NPs) to simultaneously target tumor cells and TAMs for enhancing the therapeutic effect. In these nanoclusters, the Pd-HA part was obtained by modifying hyaluronic acid (HA) on the surface of ultra-small Pd nanozymes that could target CT26 cells. Moreover, with the high peroxidase (POD) and catalase (CAT) activity of Pd nanozymes, Pd-HA NPs directly caused cancer cell death by producing H2O2 and highly toxic reactive oxygen therapy (ROS) through chemodynamic therapy (CDT). The other part of Pd NPs functioned as a carrier that linked mannose (Man) and the imiquimod molecule (R837) to obtain Pd-M@R NPs, which could specifically connect the mannose receptor of TAMs and perform targeted reprogramming of TAMs to M1 phenotype to reverse immunosuppression and further activate immunotherapy to form "double therapy". Therefore, the strategy of "double therapy" provides new sights for treating malignant tumors. STATEMENT OF SIGNIFICANCE: The bidirectional anisotropic Pd nanoclusters (Pd-HA+Pd-M@R NPs) that can simultaneously target the tumor cells and TAMs with the modification of HA and mannose, respectively. Under the biodirectional anisotropic effect, the Pd nanozymes in Pd-HA can directly kill CT 26 cells through catalyze producing toxic ROS. The Pd-M@R exhibited effectively delivery the imiquimod molecule (R837) to TAMs and specifically induced it transformed into M1 phenotype to reverse tumor immunosuppression to form the "double therapy".

Photosensitive properties, synergistic antibacterial abilities of intelligent response-type self-assembled nanoparticle TiO2@V2O5.

Representative pathogenic bacteria such as Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) are widespread in nature and pose a threat to human health. To control the propagation of these pathogens from the source, the key is to design broad-spectrum antibacterial materials to reduce the serious damage of pathogenic bacteria. At present, more and more nanoparticles are widely researched and applied due to their multi-pathway antibacterial properties, such as regulating physiology, biochemistry and physical chemistry. In this work, we synthesized a uniformly dispersed and stable spherical nanoparticle (TiO2@V2O5) synthesized by self-assembly of tianium dioxide and vanadium pentoxide. Based on its excellent photosensitive properties, TiO2@V2O5 nanoparticles have showed excellent antibacterial properties under the light irradiation due to the production of hydroxyl radicals in antibacterial and mechanism tests. In addtion, related cell and plant experiments have showed that TiO2@V2O5 nanoparticles are excellent biocompatible materials, it could be widely used in environmental pollution control, limiting the serious damage caused by pathogens.

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.

Hollow mesoporous ruthenium nanoparticles conjugated bispecific antibody for targeted anti-colorectal cancer response of combination therapy.

Combined treatment based on tumor-targeted nanoparticles has become one of the most promising anticancer strategies. Moreover, bispecific antibodies have been designed as linkers to promote the interaction between natural killer (NK) cells and tumor cells, while triggering NK cell-mediated target cell lysis. Here, we adopted a novel design that uses PEGylated hollow mesoporous ruthenium nanoparticles as a carrier to load the fluorescent anti-tumor complex ([Ru(bpy)2(tip)]2+, RBT) and a conjugate with bispecific antibodies (SS-Fc). By accurately targeting carcinoembryonic antigen overexpressed in colorectal cancer cells, HMRu@RBT-SS-Fc significantly improved selective penetration in vitro. The functionalized nanocomplex effectively engaged NK cells and possessed excellent near infrared-sensitive cytotoxicity. Systematic in vivo studies clearly demonstrated the high tumor targeting and anticancer activity in heterotopic colorectal tumor model via combined photothermal and immune therapy. This nanosystem establishes a new platform for future image-guided drug delivery and highly efficient cancer therapy.

A photothermal-triggered nitric oxide nanogenerator combined with siRNA for precise therapy of osteoarthritis by suppressing macrophage inflammation.

Although nitric oxide (NO) can be used to treat osteoarthritis (OA) by inhibiting inflammation, a method for the accurately controlled release of NO in inflammatory cells is still elusive. Herein, photothermal-triggered NO nanogenerators NO-Hb@siRNA@PLGA-PEG (NHsPP) were constructed by assembling photothermal-agents and NO molecules within nanoparticles. In the NHsPP nanoparticles the hemoglobin (Hb) nanoparticles can act as a NO carrier which can absorb near-infrared light at 650 nm (0.5 W cm-2) and convert it into heat to trigger the release of NO. Moreover, after loading Notch1-siRNA, precise treatment can be achieved. Furthermore, using the synergistic effect of photothermal therapy, the NHsPP nanoparticles achieved simultaneous treatment with NO, siRNA and PTT. Through this combination therapy, the therapeutic effect of the NHsPP nanoparticles was significantly enhanced compared to the treatment groups using only NO, siRNA or PTT. This combination therapy inhibits the inflammatory response effectively by reducing the level of pro-inflammatory cytokines and the macrophage response. Subsequently, guided by dual-modal imaging, the NHsPP nanoparticles can not only accumulate effectively in OA mice, but can also reduce the inflammatory response and efficiently prevent cartilage erosion, without causing toxic side effects in the major organs. Therefore, this novel photothermal nanoparticle-based NO-releasing system is expected to be a potential alternative for clinical inflammatory disease therapy and may provide image guidance when combined with other nanotherapy systems.

Functionalized chitosan-modified defect-related luminescent mesoporous silica nanoparticles as new inhibitors for hIAPP aggregation.

Human islet amyloid polypeptide (hIAPP or amylin) forms the amyloid deposits that is an important factor in the induction of type II diabetes. Accordingly, it is essential to efficiently and accurately inhibit the aggregation of hIAPP for the treatment and prevention of the disease. Here, defect mesoporous silica (DLMSN), with blue fluorescence, can perfectly achieve the accurate positioning in cells or organisms. DL@CS@NF cannot only specifically bind to a hIAPP monomer, but also effectively inhibit hIAPP aggregation, reduce cytotoxicity and overcome the instability and inefficiency of NF(N-Me)GA(N-Me)IL (NF). Furthermore, DL@CS@NF nanoparticles can significantly improve the survival rate of islet cells, stabilize the mitochondrial membrane potential, reduce the content of intracellular reactive oxygen species. In summary, DL@CS@NF nanoparticles may have broader implications in inhibiting the aggregation of hIAPP and reducing cytotoxicity.

Targeted hexagonal Pd nanosheet combination therapy for rheumatoid arthritis via the photothermal controlled release of MTX.

Methotrexate (MTX) is a drug that is used for the clinical treatment of rheumatoid arthritis (RA), a stubborn disease caused by over-immunization. However, the toxicity that arises as a result of poor selectivity to inflammatory cells severely limits the application of MTX. Therefore, new therapeutic strategies are needed for treating RA. Here, we describe the design and synthesis of a nanotherapy agent, Pd-Cys@MTX@RGD, which can target inflammatory cells and control MTX release. The novel hexagonal palladium (Pd) nanosheets were used as a near-infrared (NIR) photothermal agent modified with arginine-glycineaspartic acid (RGD) peptides on the surface to enhance the ability of the nanosheet targeting of inflammatory cells. In subsequent experiments, the Pd-Cys@MTX@RGD nanosheets were observed to greatly reduce the toxicity of MTX, showing controlled MTX release under irradiation of 808 nm (0.3 W cm-2). Moreover, taking advantage of the fact that MTX can be combined with multiple therapeutic methods, the photothermal therapy (PTT) of Pd nanosheets provided a compensatory effect to enhance the therapeutic efficacy of MTX. Under combination therapy, Pd-Cys@MTX@RGD was shown to effectively inhibit the inflammatory response induced by vascular endothelial growth factor (VEGF) and IL-1ß. And, in vivo, multifunctional Pd-Cys@MTX@RGD effectively inhibited the symptoms of RA by inhibiting the expression of pro-inflammatory cytokines (TNF-α,COX-2). We hope that the construction of nanomaterials can add potential value to the design of chemical drugs and therapeutic strategies for RA.

Transferrin/aptamer conjugated mesoporous ruthenium nanosystem for redox-controlled and targeted chemo-photodynamic therapy of glioma.

The blood-brain barrier (BBB) and low targeting are major obstacles for the treatment of gliomas. Accordingly, overcoming the BBB and enhancing the targeting of drugs to the glioma area are key to achieving a good therapeutic effect. Here, we have developed the mesoporous ruthenium nanosystem RBT@MRN-SS-Tf/Apt with dual targeting function. Transferrin (Tf) and aptamer AS1411 (Apt) are grafted on the surfaces of mesoporous ruthenium nanoparticles (MRN) with high loading capacity. This is achieved via redox-cleavable disulfide bonds, serving as both a capping agent and a targeting ligand, enabling the effective penetration of the blood-brain barrier and targeting the glioma. In addition, RBT@MRN-SS-Tf/Apt can specifically kill glioma cells in vitro and in vivo. Moreover, anti-tumor drugs [Ru(bpy)2(tip)]2+ (RBT) will produce reactive oxygen species and induce apoptosis of tumor cells under laser irradiation, providing photodynamic therapy (PDT) for the treatment of gliomas, and further prolonging the median survival period. The study shows that this chemical photodynamic therapy nanosystem can be used as an efficient and powerful synergistic system for the treatment of brain tumors and other brain diseases of the central nervous system. STATEMENT OF SIGNIFICANCE: In order to overcome the blood-brain barrier and low targeting, and enhance the anti-glioma activities of nanodrugs. We have developed RBT@MRN-SS-Tf/Apt with dual targeting function. It is achieved release drug via redox-cleavable disulfide bonds, and enable the effective penetration of the blood-brain barrier and targeting the glioma. Moreover, anti-tumor drugs RBT will produce reactive oxygen species and induce apoptosis of tumor cells under laser irradiation, providing photodynamic therapy (PDT) for the treatment of gliomas, and further prolonging the median survival period. Therefore, this chemical photodynamic therapy nanosystem can be used as an efficient and powerful synergistic system for the treatment of brain tumors and other brain diseases of the central nervous system.