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Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of "reprogramming" and "interfering" iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical "Trojan horse", mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis-apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.
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Apoptose , Gálio , Ferro , Humanos , Gálio/química , Gálio/farmacologia , Apoptose/efeitos dos fármacos , Ferro/metabolismo , Ferro/química , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Receptores da Transferrina/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Sulfetos/química , Sulfetos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Paraptose , Proteínas de Transporte de CátionsRESUMO
Pyroptosis is an inflammatory form of programmed cell death associated with the immune system that can be induced by reactive oxygen species (ROS). As a therapeutic strategy with better penetration depth, sonodynamic therapy (SDT) is expected to induce pyroptosis of cancer cells and boost the immune response. However, it is still a limited problem to precisely adjust the structure of sonosensitizers to exhibit satisfactory sono-catalytic properties. Herein, fluorinated titanium oxide (TiO2-xFx) sonosensitizers were developed to induce pyroptosis under ultrasound (US) to boost antitumor immune responses, enabling highly effective SDT. On the one hand, the introduction of F atoms significantly reduced the adsorption energy of TiO2-xFx for oxygen and water, which is conducive to the occurrence of sono-catalytic reactions. On the other hand, the process of F replacing O increased the oxygen vacancies of the sonosensitizer and shortened the band gap, which enabled powerful ROS generation ability under US stimulation. In this case, large amounts of ROS could effectively kill cancer cells by inducing mitochondrial damage and disrupting oxidative homeostasis, leading to significant cell pyroptosis. Moreover, SDT treatment with TiO2-xFx not only suppressed tumor proliferation but also elicited robust immune memory effects and hindered tumor recurrence. This work highlighted the importance of precisely regulating the structure of sonosensitizers to achieve efficient ROS generation for inducing pyroptosis, which sets the stage for the further development of SDT-immunotherapy.
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The immunosuppressive microenvironment of cervical cancer significantly hampers the effectiveness of immunotherapy. Herein, PEGylated manganese-doped calcium sulfide nanoparticles (MCSP) were developed to effectively enhance the antitumor immune response of the cervical cancer through gas-amplified metalloimmunotherapy with dual activation of pyroptosis and STING pathway. The bioactive MCSP exhibited the ability to rapidly release Ca2+, Mn2+, and H2S in response to the tumor microenvironment. H2S disrupted the calcium buffer system of cancer cells by interfering with the oxidative phosphorylation pathway, leading to calcium overload-triggered pyroptosis. On the other hand, H2S-mediated mitochondrial dysfunction further promoted the release of mitochondrial DNA (mtDNA), enhancing the activation effect of Mn2+ on the cGAS-STING signaling axis and thereby activating immunosuppressed dendritic cells. The released H2S acted as an important synergist between Mn2+ and Ca2+ by modulating dual signaling mechanisms to bridge innate and adaptive immune responses. The combination of MCSP NPs and PD-1 immunotherapy achieved synergistic antitumor effects and effectively inhibited tumor growth. This study reveals the potential collaboration between H2S gas therapy and metalloimmunotherapy and provides an idea for the design of nanoimmunomodulators for rational regulation of the immunosuppressive tumor microenvironment.
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Imunoterapia , Proteínas de Membrana , Piroptose , Microambiente Tumoral , Neoplasias do Colo do Útero , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/terapia , Feminino , Humanos , Camundongos , Animais , Piroptose/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Manganês/química , Manganês/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Nanopartículas/química , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cálcio/metabolismo , Camundongos Endogâmicos BALB C , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Hypochlorous acid (HClO), as a powerful oxidizer, is obtained from the oxidation of Cl- ions during the electrochemical therapy (EChT) process for cancer therapy. However, the extracellular generated HClO is inadequate to inhibit effective tumor cell death. Herein, manganese-doped potassium chloride nanocubes (MPC NCs) fabricated and modified with amphipathic polymer PEG (PMPC NCs) to function as massive three-dimensional nanoelectrodes (NEs) were developed to enhance the generation of HClO for electrochemical immunotherapy under an alternating electric field. Under an square-wave alternating current (AC) electric field, the generation of HClO was boosted by PMPC NEs due to the enlarged active surface area, enhanced mass transfer rate, and improved electrocatalytic activity. Notably, PMPC NEs upregulated the intracellular HClO concentration to induce robust immunogenic cell death (ICD) under an AC electric field. Meanwhile, the electric-triggered release of Mn2+ effectively stimulated dendritic cells (DCs) maturation. In vivo results illustrated that PMPC-mediated EChT inhibited tumor growth and triggered the promotion of the immune response to regulate the tumor immune microenvironment. Based on the potent antitumor immunity, PMPC-mediated EChT was further combined with an immune checkpoint inhibitor (αCTLA-4) to realize combined EChT-immunotherapy, which demonstrated enhanced tumor inhibition of the primary tumors and an abscopal effect on distant tumors. To summarize, our work highlights the application of electrochemical-immunotherapy technology in tumor therapy.
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Imunoterapia , Manganês , Manganês/química , Camundongos , Animais , Eletrodos , Humanos , Técnicas Eletroquímicas , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
Immunotherapy has emerged as a potential approach for breast cancer treatment. However, the rigid stromal microenvironment and low immunogenicity of breast tumors strongly reduce sensitivity to immunotherapy. To sensitize patients to breast cancer immunotherapy, hyaluronic acid-modified zinc peroxide-iron nanocomposites (Fe-ZnO2@HA, abbreviated FZOH) were synthesized to remodel the stromal microenvironment and increase tumor immunogenicity. The constructed FZOH spontaneously generated highly oxidative hydroxyl radicals (·OH) that degrade hyaluronic acid (HA) in the tumor extracellular matrix (ECM), thereby reshaping the tumor stromal microenvironment and enhancing blood perfusion, drug penetration, and immune cell infiltration. Furthermore, FZOH not only triggers pyroptosis through the activation of the caspase-1/GSDMD-dependent pathway but also induces ferroptosis through various mechanisms, including increasing the levels of Fe2+ in the intracellular iron pool, downregulating the expression of FPN1 to inhibit iron efflux, and activating the p53 signaling pathway to cause the failure of the SLC7A11-GSH-GPX4 signaling axis. Upon treatment with FZOH, 4T1 cancer cells undergo both ferroptosis and pyroptosis, exhibiting a strong immunogenic response. The remodeling of the tumor stromal microenvironment and the immunogenic response of the cells induced by FZOH collectively compensate for the limitations of cancer immunotherapy and significantly enhance the antitumor immune response to the immune checkpoint inhibitor αPD-1. This study proposes a perspective for enhancing immune therapy for breast cancer.
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Neoplasias da Mama , Neoplasias , Humanos , Feminino , Neoplasias da Mama/terapia , Ácido Hialurônico , Imunoterapia , Peróxidos , Zinco , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Metal-based nanomaterials have attracted broad attention recently due to their unique biological physical and chemical properties after entering tumor cells, namely biological effects. In particular, the abilities of Ca2+ to modulate T cell receptors activation, K+ to regulate stem cell differentiation, Mn2+ to activate the STING pathway, and Fe2+/3+ to induce tumor ferroptosis and enhance catalytic therapy, make the metal ions and metal-based nanomaterials play crucial roles in the cancer treatments. Therefore, due to the superior advantages of metal-based nanomaterials and the characteristics of the tumor microenvironment, we will summarize the recent progress of the anti-tumor biological effects of metal-based nanomaterials. Based on the different effects of metal-based nanomaterials on tumor cells, this review mainly focuses on the following five aspects: (1) metal-enhanced radiotherapy sensitization, (2) metal-enhanced catalytic therapy, (3) metal-enhanced ferroptosis, (4) metal-enhanced pyroptosis, and (5) metal-enhanced immunotherapy. At the same time, the shortcomings of the biological effects of metal-based nanomaterials on tumor therapy are also discussed, and the future research directions have been prospected. The highlights of promising biosafety, potent efficacy on biological effects for tumor therapy, and the in-depth various biological effects mechanism studies of metal-based nanomaterials provide novel ideas for the future biological application of the nanomaterials.
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The occurrence and development of inflammatory bowel diseases (IBDs) are inextricably linked to the excessive production of reactive oxygen species (ROS). Thus, there is an urgent need to develop innovative tactics to combat IBDs and scavenge excess ROS from affected areas. Herein, silicon hydrogen nanoparticles (SiH NPs) with ROS-scavenging ability were prepared by etching Si nanowires (NWs) with hydrogen fluoride (HF) to alleviate the symptoms associated with IBD by orally targeting the inflamed colonic sites. The strong reductive Si-H bonds showed excellent stability in the gastric and intestinal fluids, which exhibited efficient ROS-scavenging effects to protect cells from high oxidative stress-induced death. After oral delivery, the negatively charged SiH NPs were specifically adsorbed to the positively charged inflammatory epithelial tissues of the colon for an extended period via electrostatic interactions to prolong the colonic residence time. SiH NPs exhibited significant preventive and therapeutic effects in dextran sodium sulfate-induced prophylactic and therapeutic mouse models by inhibiting colonic shortening, reducing the secretion of pro-inflammatory cytokines, regulating macrophage polarization, and protecting the colonic barrier. As determined using 16S rDNA high-throughput sequencing, the oral administration of SiH NPs treatment led to changes in the abundance of the intestinal microbiome, which improved the bacterial diversity and restored the relative abundance of beneficial bacteria after the inflamed colon. Overall, our findings highlight the broad application of SiH-based anti-inflammatory drugs in the treatment of IBD and other inflammatory diseases.
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Doenças Inflamatórias Intestinais , Nanoestruturas , Silício , Animais , Camundongos , Anti-Inflamatórios/uso terapêutico , Bactérias , Colo , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/tratamento farmacológico , Espécies Reativas de Oxigênio , Silício/farmacologia , Silício/uso terapêuticoRESUMO
Bioactive inorganic nanomaterials and the biological effects of metal ions have attracted extensive attention in tumor therapy in recent years. Vanadium (V), as a typical bioactive metal element, regulates a variety of biological functions. However, its role in antitumor therapy remains to be revealed. Herein, biodegradable vanadium disulfide (VS2) nanosheets (NSs) were prepared as a responsive gas donor and bioactive V source for activating cancer immunotherapy in combination with immune-checkpoint blockade therapy. After PEGylation, VS2-PEG exhibited efficient glutathione (GSH) depletion and GSH-activated hydrogen sulfide (H2S) release. Exogenous H2S caused lysosome escape and reduced adenosine triphosphate (ATP) synthesis in tumor cells by interfering with the mitochondrial membrane potential and inducing acidosis. In addition, VS2-PEG degraded into high-valent vanadate, leading to Na+/K+ ATPase inhibition, potassium efflux, and interleukin (IL)-1ß production. Together with further induction of ferroptosis and immunogenic cell death, a strong antitumor immune response was stimulated by reversing the immunosuppressive tumor microenvironment. Moreover, the combined treatment of VS2-PEG and α-PD-1 amplified antitumor therapy, significantly suppressed tumor growth, and further elicited robust immunity to effectively defeat tumors. This work highlights the biological effects of vanadium for application in cancer treatment.
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Neoplasias , Vanadatos , Vanadatos/farmacologia , Vanadatos/uso terapêutico , Inibidores de Checkpoint Imunológico , Vanádio , Imunoterapia , Glutationa , Neoplasias/tratamento farmacológicoRESUMO
Tumor immunotherapy is an important tool in oncology treatment. However, only a small percentage of patients have an effective immune response to tumor immunotherapy due to the poor infiltration of pro-inflammatory immune cells in immune "cold" tumors and an immunosuppressive network in the tumor microenvironment (TME). Ferroptosis has been widely used as a novel strategy to enhance tumor immunotherapy. Herein, manganese molybdate nanoparticles (MnMoOx NPs) depleted the highly expressed glutathione (GSH) in tumors and inhibited glutathione peroxidase 4 (GPX4) expression, thus triggering ferroptosis, inducing immune cell death (ICD), further releasing damage-associated molecular patterns (DAMPs), and enhancing tumor immunotherapy. Furthermore, MnMoOx NPs can efficiently suppress tumors, promote the maturation of dendritic cells (DCs), infiltrate T cells, and reverse the immunosuppressive microenvironment, making the tumor an immune "hot" tumor. Combination with an immune checkpoint inhibitor (ICI) (α-PD-L1) further enhanced the anti-tumor effect and inhibited metastases as well. The work provides a new idea for the development of nonferrous inducers of ferroptosis to enhance cancer immunotherapy.
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Ferroptose , Nanopartículas , Neoplasias , Humanos , Manganês , Imunoterapia , Glutationa , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Autologous cancer vaccines constructed by nonproliferative whole tumor cells or tumor lysates together with appropriate adjuvants represent a promising strategy to suppress postsurgical tumor recurrence. Inspired by the potency of cytosolic double-stranded DNA (dsDNA) in initiating anticancer immunity by activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, we herein report the concise synthesis of a cGAS-STING agonist through dsDNA-templated biomineralization growth of calcium carbonate (CaCO3) microparticles. The yielded DNA@CaCO3 can activate the intracellular cGAS-STING pathway of dendritic cells (DCs) by promoting endosomal escape of dsDNA, triggering their maturation and activation as a potent immune stimulator. Upon intratumoral injection, DNA@CaCO3 can reverse the immunosuppressive tumor microenvironment by simultaneously provoking innate and adaptive antitumor immunity, thereby effectively suppressing the growth of murine CT26 and B16-F10 tumors in mice. Furthermore, via CaCO3-based biomineralization of complete tumor lysates, we constructed a personalized autologous cancer vaccine with intrinsic cGAS-STING activation capacity that could provoke tumor-specific immune responses to not only delay the growth of challenged tumors but also synergize with anti-PD-1 immunotherapy to suppress postsurgical tumor recurrence. This study highlights a CaCO3-based biomineralization method to prepare autologous cancer vaccines in a concise manner, which is promising for personalized immunotherapy and clinical translation.
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Vacinas Anticâncer , Neoplasias , Camundongos , Animais , Biomineralização , Recidiva Local de Neoplasia , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , DNA , Neoplasias/terapia , Imunoterapia/métodos , Microambiente TumoralRESUMO
Intracerebral hemorrhage (ICH) remains a significant cause of morbidity and mortality around the world, and surgery is still the most direct and effective way to remove ICH. However, the potential risks brought by surgery, such as normal brain tissue damage, post-operative infection, and difficulty in removing deep hematoma, are still the main problems in the surgical treatment of ICH. Activation of the peroxisome proliferator-activated receptor gamma (PPARγ) is reported to show a good therapeutic effect in hematoma clearance. Herein, a magnetic targeting nanocarrier loaded with a PPARγ agonist (15d-PGJ2-MNPs) is synthesized, which could be magnetically targeted and enriched in the area of the hematoma after intravenous injection. Subsequent application of focusing ultrasound (FUS) could enhance drug diffusion, which activates the PPARγ receptors on macrophages around the hematoma for better hematoma clearance. The 15d-PGJ2-MNP treatment alleviates brain injury, accelerates hematoma clearance, attenuates neuroinflammation, reduces brain edema and significantly improves the deficits in sensory and motor function and spatial learning ability in the ICH mouse model. This work proposes an effective magnetic targeting plus FUS method to treat ICH, highlighting its great potential in the treatment of hemorrhagic stroke.
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Hemorragia Cerebral , PPAR gama , Camundongos , Animais , PPAR gama/agonistas , PPAR gama/metabolismo , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/terapia , Hemorragia Cerebral/complicações , Encéfalo/metabolismo , Hematoma/terapia , Hematoma/tratamento farmacológico , Modelos Animais de Doenças , Fenômenos MagnéticosRESUMO
Oxygen-deficient molybdenum oxide (MoOX ) nanomaterials are prepared as novel nanosensitizers and TME-stimulants for ultrasound (US)-enhanced cancer metalloimmunotherapy. After PEGylation, MoOX -PEG exhibits efficient capability for US-triggered reactive oxygen species (ROS) generation and glutathione (GSH) depletion. Under US irradiation, MoOX -PEG generates a massive amount of ROS to induce cancer cell damage and immunogenic cell death (ICD), which can effectively suppress tumor growth. More importantly, MoOX -PEG itself further stimulates the maturation of dendritic cells (DCs) and triggeres the activation of the cGAS-STING pathway to enhance the immunological effect. Due to the robust ICD induced by SDT and efficient DC maturation stimulated by MoOX -PEG, the combination treatment of MoOX -triggered SDT and aCTLA-4 further amplifies antitumor therapy, inhibits cancer metastases, and elicits robust immune responses to effectively defeat abscopal tumors.
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Neoplasias , Óxidos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Molibdênio , Neoplasias/tratamento farmacológico , Hipóxia , Oxigênio/metabolismo , Linhagem Celular TumoralRESUMO
Bioactive materials are a special class of biomaterials that can react in vivo to induce a biological response or regulate biological functions, thus achieving a better curative effect than traditional inert biomaterials. For cancer theranostics, compared with organic or polymer nanomaterials, inorganic nanomaterials possess unique physical and chemical properties, have stronger mechanical stability on the basis of maintaining certain bioactivity, and are easy to be compounded with various carriers (polymer carriers, biological carriers, etc.), so as to achieve specific antitumor efficacy. After entering the nanoscale, due to the nano-size effect, high specific surface area and special nanostructures, inorganic nanomaterials exhibit unique biological effects, which significantly influence the interaction with biological organisms. Therefore, the research and applications of bioactive inorganic nanomaterials in cancer theranostics have attracted wide attention. In this review, we mainly summarize the recent progress of bioactive inorganic nanomaterials in cancer theranostics, and also introduce the definition, synthesis and modification strategies of bioactive inorganic nanomaterials. Thereafter, the applications of bioactive inorganic nanomaterials in tumor imaging and antitumor therapy, including tumor microenvironment (TME) regulation, catalytic therapy, gas therapy, regulatory cell death and immunotherapy, are discussed. Finally, the biosafety and challenges of bioactive inorganic nanomaterials are also mentioned, and their future development opportunities are prospected. This review highlights the bioapplication of bioactive inorganic nanomaterials.
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Nanoestruturas , Neoplasias , Humanos , Medicina de Precisão , Nanomedicina Teranóstica/métodos , Nanoestruturas/uso terapêutico , Nanoestruturas/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Materiais Biocompatíveis , Polímeros/química , Microambiente TumoralRESUMO
Oxidative stress and mitochondrial damage are the main mechanisms of ischemia-reperfusion injury in ischemic stroke. Herein, cerium oxide nanoparticles with powerful free radical scavenging ability were used as carriers to load dl-3-n-butylphthalide (NBP-CeO2 NPs) for the combined treatment of ischemic stroke. NBP-CeO2 NPs could eliminate reactive oxygen species (ROS) in mouse brain microvascular endothelial cells and hippocampal neurons after oxygen-glucose deprivation/reoxygenation (OGD/R), and also save mitochondrial membrane potential, morphology, and function, thus alleviating the in vitro blood brain barrier (BBB) disruption and neuronal apoptosis. In the middle cerebral artery embolization/recanalization (MCAO/R) mouse model, the NBP-CeO2 NPs also possessed superior ROS scavenging ability, protected mitochondria, and preserved BBB integrity, thereby reducing cerebral infarction and cerebral edema and inhibiting neuroinflammation and neuronal apoptosis. The long-term neurobehavioral tests indicated that the NBP-CeO2 NPs significantly improved sensorimotor function and spatial learning ability by promoting angiogenesis after ischemic stroke. Therefore, the NBP-CeO2 NPs provided a novel therapeutic approach for ischemic stroke by combining antioxidant and neurovascular repair abilities, highlighting its wide application in ischemia-reperfusion injury.
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AVC Isquêmico , Nanopartículas , Traumatismo por Reperfusão , Animais , Camundongos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Espécies Reativas de Oxigênio , Células Endoteliais , Traumatismo por Reperfusão/tratamento farmacológicoRESUMO
Gas-mediated sonodynamic therapy (SDT) has the potential to become an effective strategy to improve the therapeutic outcome and survival rate of cancer patients. Herein, titanium sulfide nanosheets (TiSX NSs) are prepared as cascade bioreactors for sequential gas-sonodynamic cancer therapy. TiSX NSs themselves as hydrogen sulfide (H2 S) donors can burst release H2 S gas. Following H2 S generation, TiSX NSs are gradually degraded to become S-defective and partly oxidized into TiOX on their surface, which endows TiSX NSs with high sonodynamic properties under ultrasound (US) irradiation. In vitro and in vivo experiments show the excellent therapeutic effects of TiSX NSs. In detail, large amounts of H2 S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H2 S gas also plays important roles in modulating and activating the immune system to effectively inhibit pulmonary metastasis. Finally, the metabolizable TiSX NSs are excreted out of the body without inducing any significant long-term toxicity. Collectively, this work establishes a cascade bioreactor of TiSX NSs with satisfactory H2 S release ability and excellent ROS generation properties under US irradiation for programmed gas-sonodynamic cancer therapy.
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Sulfeto de Hidrogênio , Neoplasias , Humanos , Espécies Reativas de Oxigênio/metabolismo , Reatores Biológicos , Trifosfato de AdenosinaRESUMO
Spinal cord regeneration after a spinal cord injury (SCI) remains a difficult challenge due to the complicated inflammatory microenvironment and neuronal damage at the injury sites. In this study, retinoic acid (RA) and curcumin (Cur) were co-loaded with bovine serum albumin (BSA) self-assembly to obtain RA@BSA@Cur nanoparticles (NPs) for SCI treatment. Cur, as an antioxidant drug, facilitated reactive oxygen species (ROS) scavenging, and decreased the amount of inflammatory factors secreted by macrophages, while RA could enhance neurite extensions and neural differentiation. The constructed RA@BSA@Cur NPs not only induced polarization of macrophages toward pro-regenerative phenotypes and markedly reduced the inflammatory response of macrophages or microglia, but also increased neurite length in PC12 cells and neuronal differentiation of bone marrow mesenchymal stem cells, improved the differentiation of neural stem cells (NSCs) into ß3-tubulin+ neurons, and reversed the pro-astrocyte differentiation effect of inflammatory cytokines on NSCs. In vivo experiments revealed that RA@BSA@Cur NPs regulated the phenotypic polarization of macrophages, inhibited the release of inflammatory mediators, promoted functional neuron regeneration and motor function, and further inhibited scar tissue formation. This study highlighted that the BSA-based biomimetic nanomaterials could be used as ROS scavengers and nerve regeneration promoters for treating SCI.
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Sonodynamic therapy (SDT) has garnered extensive attention as a noninvasive treatment for deep tumors. Furthermore, imiquimod (R837), an FDA-approved toll-like receptor 7 agonist, is commonly used in clinical settings as an immune adjuvant. We prepared an activatable sonodynamic sensitizer platform (MR) based on glutathione-sensitive disulfide bonds linking Leu-MB, the reduced form of methylene blue (MB), and R837 to achieve efficient combinatory SDT and immunotherapy for tumors without harming normal tissues. We also used the amphiphilic polymer C18PMH-PEG to create self-assembled MB-R837-PEG (MRP) nanoparticles for immunosonodynamic therapy (iSDT). iSDT is a cancer treatment that combines activatable SDT and immunotherapy. Our iSDT demonstrated an excellent sonodynamic effect only at the tumor site, demonstrating high specificity in killing tumor cells when compared to SDT reported in the literature. The iSDT improves its tumor-killing effect by inducing an immune response, which is accomplished by secreted immune adjuvants in the tumor site. MRP was selectively activated by glutathione in the tumor microenvironment to release MB and R837, exhibiting excellent antitumor sonodynamic and immune responses. In addition, when combined with an α-PD-L1 antibody for immune checkpoint blockade, this therapy effectively inhibited tumor metastasis. Furthermore, mice treated with iSDT and α-PD-L1 antibody did not develop tumors even after tumor reinoculation, indicating that long-term immune memory was achieved. The concept of sonodynamic sensitizer preparation as a next-generation iSDT based on a noninvasive synergistic therapeutic modality applicable in the near future is presented in this study.
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Imiquimode , Nanopartículas , Animais , Camundongos , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Antígeno B7-H1 , Linhagem Celular Tumoral , Glutationa , Imiquimode/farmacologia , Imunoterapia , Nanopartículas/químicaRESUMO
Hydrogen can be used as an anti-cancer treatment. However, the continuous generation of H2 molecules within the tumor is challenging. Magnesium (Mg) and its alloys have been extensively used in the clinic as implantable metals. Here we develop, by decorating platinum on the surface of Mg rods, a Mg-based galvanic cell (MgG), which allows the continuous generation of H2 in an aqueous environment due to galvanic-cell-accelerated water etching of Mg. By implanting MgG rods into a tumor, H2 molecules can be generated within the tumor, which induces mitochondrial dysfunction and intracellular redox homeostasis destruction. Meanwhile, the Mg(OH)2 residue can neutralize the acidic tumor microenvironment (TME). Such MgG rods with the micro-galvanic cell structure enable hydrogen therapy to inhibit the growth of tumors, including murine tumor models, patient-derived xenografts (PDX), as well as VX2 tumors in rabbits. Our research suggests that the galvanic cells for hydrogen therapy based on implantable metals may be a safe and effective cancer treatment.
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Neoplasias , Microambiente Tumoral , Ligas , Animais , Humanos , Hidrogênio/farmacologia , Magnésio , Camundongos , Neoplasias/tratamento farmacológico , CoelhosRESUMO
Sonodynamic therapy (SDT) has attracted widespread interest in biomedicine, owing to its novel and noninvasive therapeutic method triggered by ultrasound (US). Herein, the Ti3C2 MXene nanosheets (Ti3C2 NSs) are developed as good sonosensitizers via a two-step method of chemical exfoliation and high-temperature treatment. With the high-temperature treatment, the oxygen defect of Ti3C2 MXene nanosheets (H-Ti3C2 NSs) is greatly increased. Therefore, the electron (e-) and hole (h+) generated by US can be separated faster due to the improved degree of oxidation, and then the recombination of e--h+ can be prevented with the abundant oxygen defect under US irradiation, which induced the sonodynamic efficiency greatly to improve around 3.7-fold compared with Ti3C2 NSs without high-temperature treatment. After PEGylation, the H-Ti3C2-PEG NSs show good stability and biocompatibility. In vitro studies exhibit that the inherent property of mild photothermal effect can promote the endocytosis of H-Ti3C2-PEG NSs, which can improve the SDT efficacy. In vivo studies further display that the increased blood supply by the mild photothermal effect can significantly relieve hypoxia in the tumor microenvironment, showing photothermal therapy (PTT) enhanced SDT. Most importantly, the H-Ti3C2-PEG NSs can be biodegraded and excreted out of the body, showing no significant long-term toxicity. Our work develops the defective H-Ti3C2 NSs as high-efficiency and safe sonosensitizers for photothermal-enhanced SDT of cancer, extending the biomedical application of MXene-based nanoplatforms.