Cyclometalated ruthenium complexes overcome cisplatin resistance through PI3K/mTOR/Nrf2 signaling pathway.

Currently, cisplatin resistance remains a primary clinical obstacle in the successful treatment of non-small cell lung cancer. Here, we designed, synthesized, and characterized two novel cyclometalated Ru(II) complexes, [Ru(bpy)2(1-Ph-7-OCH3-IQ)] (PF6) (bpy = 2,2'-bipyridine, IQ = isoquinoline, RuIQ7)and [Ru(bpy)2(1-Ph-6,7-(OCH3)2-IQ)] (PF6) (RuIQ8). As experimental controls, we prepared complex [Ru(bpy)2(1-Ph-IQ)](PF6) (RuIQ6) lacking a methoxy group in the main ligand. Significantly, complexes RuIQ6-8 displayed higher in vitro cytotoxicity when compared to ligands, precursor cis-[Ru(bpy)2Cl2], and clinical cisplatin. Mechanistic investigations revealed that RuIQ6-8 could inhibit cell proliferation by downregulating the phosphorylation levels of Akt and mTOR proteins, consequently affecting the rapid growth of human lung adenocarcinoma cisplatin-resistant cells A549/DDP. Moreover, the results from qRT-PCR demonstrated that these complexes could directly suppress the transcription of the NF-E2-related factor 2 gene, leading to the inhibition of downstream multidrug resistance-associated protein 1 expression and effectively overcoming cisplatin resistance. Furthermore, the relationship between the chemical structures of these three complexes and their anticancer activity, ability to induce cell apoptosis, and their efficacy in overcoming cisplatin resistance has been thoroughly examined and discussed. Notably, the toxicity test conducted on zebrafish embryos indicated that the three Ru-IQ complexes displayed favorable safety profiles. Consequently, the potential of these developed compounds as innovative therapeutic agents for the efficient and low-toxic treatment of NSCLC appears highly promising.

A trispecific antibody induces potent tumor-directed T-cell activation and antitumor activity by CD3/CD28 co-engagement.

Aim: A novel CD19xCD3xCD28 trispecific antibody with a tandem single-chain variable fragments (scFv) structure was developed for the treatment of B-cell malignancies. Methods: The trispecific antibody in inducing tumor-directed T-cell activation and cytotoxicity was evaluated in vitro and in vivo and compared with its bispecific counterpart BiTE-CD19xCD3 lacking a CD28-targeting domain. Results: The trispecific antibody with a co-stimulatory domain exhibited augmented T-cell activation and memory T-cell differentiation capability and it induced faster tumor cell lysis than the bispecific antibody. RNAseq analysis revealed that the trispecific antibody modulates CD3/TCR complex-derived signal and upregulates antiapoptotic factors to influence the survival of T cells. Conclusion: By CD3/CD28 co-engagement, the trispecific antibody demonstrated its advantages in T-cell immunity and potential use as a more powerful and long-lasting T-cell engager.

T-cell based immunotherapies are a type of treatment that stimulates the body's own immune system to fight cancer. They have grown in popularity in recent years and have had impressive results in cancer treatment. One type of T-cell immunotherapy is a T-cell engager antibody. This is a type of molecule that redirects the body's immune cells to recognise and kill cancer cells. In this study, we developed a new type of T-cell engager antibody to treat two types of blood and bone marrow cancer. The antibody works by joining immune cells and cancer cells close together, to help activate the immune cells for cancer killing. This new type of T-cell engager antibody worked better than previous versions. It helped the immune cells survive longer and kill cancer more effectively. This means the new antibody might be better at treating people who have these types of cancers, but more testing in humans needs to be done.

Mitochondria-targeted cyclometalated iridium (III) complexes: Dual induction of A549 cells apoptosis and autophagy.

In this study, we synthesized 4 cyclometalated iridium complexes using N-(1,10-phenanthrolin-5-yl)picolinamide (PPA) as the main ligand, denoted as [Ir(ppy)2PPA]PF6 (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)2PPA]PF6 (bzq = benzo[h]quinoline, Ir2), [Ir(dfppy)2PPA]PF6 (dfppy = 2-(3,5-difluorophenyl)pyridine, Ir3), and [Ir(thpy)2PPA]PF6 (thpy = 2-(thiophene-2-yl)pyridine, Ir4). Compared to cisplatin and oxaliplatin, all four complexes exhibited significant anti-tumor activity. Among them, Ir2 demonstrated higher cytotoxicity against A549 cells, with an IC50 value of 1.6 ± 0.2 µM. The experimental results indicated that Ir2 primarily localized in the mitochondria, inducing a large amount of reactive oxygen species (ROS) generation, that decreased in mitochondrial membrane potential (MMP), reduced ATP production, and further impaired mitochondrial function, leading to cytochrome c release. Additionally, Ir2 caused cell cycle arrest at the S phase and induced apoptosis through the AKT-mediated signaling pathway. Further investigations revealed that Ir2 could simultaneously induce both apoptosis and autophagy in A549 cells, with the latter acting as a non-protective mechanism that promoted cell death. More importantly, Ir2 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. Consequently, these newly developed Ir(III) complexes show great potential in the development of novel and low-toxicity anticancer agents.

Cyclometalated ruthenium (II) complexes induced HeLa cell apoptosis through intracellular reductive injury.

The main challenge of cancer chemotherapy is the resistance of tumor cells to oxidative damage. Herein, we proposed a novel antitumor strategy: cyclic metal­ruthenium (Ru) complexes mediate reductive damage to kill tumor cells. We designed and synthesized Ru(II) complexes with ß-carboline as ligands: [Ru (phen)2(NO2-Ph-ßC)](PF6) (RußC-7) and [Ru(phen)2(1-Ph-ßC)](PF6) (RußC-8). In vitro experimental results showed that RußC-7 and RußC-8 can inhibit cell proliferation, promote mitochondrial abnormalities, and induce DNA damage. Interestingly, RußC-7 with SOD activity could reduce intracellular reactive oxygen species (ROS) levels, while RußC-8 has the opposite effect. Accordingly, this study identified the reductive damage mechanism of tumor apoptosis, and may provide a new ideas for the design of novel metal complexes.

Ir(IV) and Ir(III) in situ transition promotes ROS generation for eradicating multidrug-resistant bacterial infection.

Whether reactive oxygen species are a consequence or a cause of antibacterial activity is not fully known. A glutathione (GSH)-mediated oxidative defense mechanism is an important factor against bacterial infection. Reactive oxygen species (ROS) storm-mediated bacterial death by depleting GSH is also considered an effective strategy. Therefore, we designed and synthesized hybrid iridium ruthenium oxide nanozymes (IrRuOx NPs), where IrRuOx NPs alternately consume GSH through double redox electron pair auto-valent cycles, while an IrRuOx NP-mediated Fenton-like reaction occurs to realize an ROS storm, which in turn mediates lipid peroxidation to promote bacterial death. The results showed that IrRuOx NPs can effectively inhibit and kill Gram-positive and Gram-negative bacteria in vitro, and can be used as broad-spectrum antibiotics. Importantly, the wound and sepsis models of MRSA infection confirmed the efficient antibacterial activity of IrRuOx NPs in vivo. Accordingly, this study provides a new idea for metal oxide hybrid nanoenzymes and their biological functions.

Ruthenium(II) complexes as mitochondrial inhibitors of topoisomerase induced A549 cell apoptosis.

Two new ruthenium(II) complexes [Ru(dip)2(PPßC)]PF6 (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)2(PPßC)]PF6 (Ru2, phen = 1, 10-phenanthroline) with ß-carboline derivative PPßC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC50 values ranging from 0.5 to 3.6 µM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.

Mitochondria-targeted cyclometalated iridium-ß-carboline complexes as potent non-small cell lung cancer therapeutic agents.

Natural products and metals play a crucial role in cancer research and the development of antitumor drugs. We designed and synthesized three new carboline-based cyclometalated iridium complexes [Ir(C-N)2(PPßC)](PF6), where PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide, C-N = 2-phenylpyridine (ppy, Ir1), 2-(2,4-difluorophenyl) pyridine (dfppy, Ir2), 7,8-benzoquinoline (bzq, Ir3), by combining iridium with ß-carboline derivative. These iridium complexes exhibited high potential antitumor effects after being promptly taken up by A549 cells. Accumulating in mitochondria rapidly and preferentially, Ir1-3 caused a series of changes in mitochondrial events, including the loss of mitochondrial membrane potential, the depletion of cellular ATP, and the elevation of reactive oxygen species, leading to significant death of A549 cells. Moreover, the activation of intracellular caspase pathway and apoptosis was further validated to contribute to iridium complexes-induced cytotoxicity. These novel iridium complexes exerted a prominent inhibitory effect on tumor growth in a three-dimensional multicellular tumor spheroid model.

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.

A hybrid nanozymes in situ oxygen supply synergistic photothermal/chemotherapy of cancer management.

Hypoxia in the solid tumor microenvironment (TME) can easily induce tumor recurrence, metastasis, and drug resistance. The use of man-made nanozymes is considered to be an effective strategy for regulating hypoxia in the TME. Herein, Ru@MnO2 nanozymes were constructed via an in situ reduction method, and they showed excellent photothermal conversion efficiency and catalytic activity. The anti-tumor drug DOX with fluorescence was loaded on the Ru@MnO2 nanozymes, and an erythrocyte membrane was further coated on the surface of the Ru@MnO2 nanozymes to construct nanozymes with on-demand release abilities. The erythrocyte membrane (RBCm) enhances the biocompatibility of the Ru@MnO2 nanozymes and prolongs their circulation time in the blood. Ru@MnO2 nanozymes can catalyze endogenous H2O2 to produce O2 to relieve hypoxia in the TME to enhance the efficacy of the photothermal therapy/chemotherapy of cancer. In vitro studies confirmed that the Ru@MnO2 nanozymes showed good tumor penetration abilities and a synergistic anti-tumor effect. Importantly, both in vivo and in vitro studies have confirmed that the oxygen supply in situ enhanced the efficacy of the PTT/chemotherapy of cancer. Accordingly, this study demonstrated that Ru@MnO2 nanozymes can be used as an effective integrated system allowing catalysis, photothermal therapy, and chemotherapy for cancer management.

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.

Microbubbles in combination with focused ultrasound for the delivery of quercetin-modified sulfur nanoparticles through the blood brain barrier into the brain parenchyma and relief of endoplasmic reticulum stress to treat Alzheimer's disease.

The delivery of drugs across the blood-brain barrier (BBB) effectively and safely is one of the major challenges in the treatment of neurodegenerative diseases. In this work, we constructed a nano-system using microbubbles to promote the crossing of drugs across the BBB, where microbubbles in combination with focused ultrasound were used to mediate the transient opening of the BBB and delivery of nanomedicines. This system (Qc@SNPs-MB) was formed by embedding quercetin-modified sulfur nanoparticles (Qc@SNPs) in microbubbles (MB). Qc@SNPs-MB was destroyed instantly when exposed to ultrasonic pulses, and it enhanced the permeability of the blood vessels, resulting in the brief opening of the BBB owing to the "sonoporation" effect. Also, Qc@SNPs were released from the outer shell of the microbubbles and entered the brain across the open BBB, accumulating in the brain parenchyma. Due to the rapid accumulation of Qc@SNPs in the brain, it effectively reduced neuronal apoptosis, inflammatory response, calcium homeostasis imbalance, and oxidative stress, which are all mediated by endoplasmic reticulum stress, and protected nerve cells, thus treating Alzheimer's disease (AD) effectively. The Morris water maze experiment showed that the learning ability and memory ability of the AD mice treated with Qc@SNPs were significantly improved, and no obvious side effects were found. Therefore, Qc@SNPs-MB combined with ultrasound can provide an effective and safe drug delivery method for the treatment of neurodegenerative diseases and a promising strategy for endoplasmic reticulum stress therapy.

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.

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.

Bacteria-Responsive Biomimetic Selenium Nanosystem for Multidrug-Resistant Bacterial Infection Detection and Inhibition.

Multidrug-resistant (MDR) bacterial infections are a severe threat to public health owing to their high risk of fatality. Noticeably, the premature degradation and undeveloped imaging ability of antibiotics still remain challenging. Herein, a selenium nanosystem in response to a bacteria-infected microenvironment is proposed as an antibiotic substitute to detect and inhibit methicillin-resistant Staphylococcus aureus (MRSA) with a combined strategy. Using natural red blood cell membrane (RBCM) and bacteria-responsive gelatin nanoparticles (GNPs), the Ru-Se@GNP-RBCM nanosystem was constructed for effective delivery of Ru-complex-modified selenium nanoparticles (Ru-Se NPs). Taking advantage of natural RBCM, the immune system clearance was reduced and exotoxins were neutralized efficiently. GNPs could be degraded by gelatinase in pathogen-infected areas in situ; therefore, Ru-Se NPs were released to destroy the bacteria cells. Ru-Se NPs with intense fluorescence imaging capability could accurately monitor the infection treatment process. Moreover, excellent in vivo bacteria elimination and a facilitated wound healing process were confirmed by two kinds of MRSA-infected mice models. Overall, the above advantages proved that the prepared nanosystem is a promising antibiotic alternative to combat the ever-threatening multidrug-resistant bacteria.

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.

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.