RESUMEN
The activation of cellular ferroptosis is promising in tumor therapy. However, ferroptosis is parallelly inhibited by antiferroptotic substances, including glutathione peroxidase 4 (GPX4), dihydroorotate dehydrogenase (DHODH), and ferroptosis suppressor protein 1 (FSP1). Thus, it is highly desirable, yet challenging, to simultaneously suppress these three antiferroptotic substances for activating ferroptosis. Here, we rationally designed a hollow iron-doped SiO2-based nanozyme (FeSHS) loaded with brequinar (BQR) and lificiguat (YC-1), named FeSHS/BQR/YC-1-PEG, for tumor ferroptosis activation. FeSHS were developed through the continuous etching of SiO2 nanoparticles by iron ions, which exhibit pH/glutathione-responsive biodegradability, along with mimicking the activities of peroxidase, glutathione oxidase, and NAD(P)H oxidase. Specifically, glutathione depletion and NAD(P)H oxidation by FeSHS will suppress the expression of GPX4 and inhibit FSP1 by disrupting the NAD(P)H/FSP1/ubiquinone axis. In addition, the released BQR can suppress the expression of DHODH. Meanwhile, YC-1 is able to increase the cellular polyunsaturated fatty acids (PUFAs) by destroying the HIF-1α/lipid droplet axis. The elevation of levels of iron and PUFAs while simultaneously disrupting the GPX4/DHODH/FSP1 inhibitory pathways by our designed nanoplatform displayed high therapeutic efficacy both in vitro and in vivo. This work elucidates rationally designing smart nanoplatforms for ferroptosis activation and future tumor treatments.
Asunto(s)
Neoplasias de la Mama , Ferroptosis , Hierro , Dióxido de Silicio , Dióxido de Silicio/química , Ferroptosis/efectos de los fármacos , Humanos , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ratones , Hierro/química , Hierro/metabolismo , Femenino , Antineoplásicos/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Ensayos de Selección de Medicamentos Antitumorales , Nanopartículas/químicaRESUMEN
Ferroptosis, an iron- and reactive oxygen species (ROS)-dependent cell death, holds significant promise for tumor therapy due to its ability to induce lipid peroxidation (LPO) and trigger antitumor immune responses. However, elevated cholesterol levels in cancer cells impede ferroptosis and compromise immune function. Here, a novel nanozyme, Fe-MOF/CP, composed of iron metal-organic framework (Fe-MOF) nanoparticles loaded with cholesterol oxidase and PEGylation for integrated ferroptosis and immunotherapy is introduced. Fe-MOF/CP depletes cholesterol and generates hydrogen peroxide, enhancing ROS levels and inducing LPO, thereby promoting ferroptosis. This process disrupts lipid raft integrity and downregulates glutathione peroxidase 4 and ferroptosis suppressor protein 1, further facilitating ferroptosis. Concurrently, Fe-MOF/CP augments immunogenic cell death, reduces programmed death-ligand 1 expression, and revitalizes exhausted CD8+ T cells. In vivo studies demonstrate significant therapeutic efficacy in abscopal, metastasis, and recurrent tumor models, highlighting the robust antitumor immune responses elicited by Fe-MOF/CP. This study underscores the potential of Fe-MOF/CP as a multifunctional therapeutic agent that combines ferroptosis and immunotherapy, offering a promising strategy for effective and durable cancer treatment.
Asunto(s)
Colesterol , Modelos Animales de Enfermedad , Ferroptosis , Inmunoterapia , Ferroptosis/efectos de los fármacos , Animales , Inmunoterapia/métodos , Ratones , Colesterol/metabolismo , Nanopartículas , Estructuras Metalorgánicas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Ratones Endogámicos C57BL , Línea Celular TumoralRESUMEN
The activation of ferroptosis presents a versatile strategy for enhancing the antitumor immune responses in cancer therapy. However, developing ferroptosis inducers that combine high biocompatibility and therapeutic efficiency remains challenging. In this study, we propose a novel approach using biological nanoparticles derived from outer membrane vesicles (OMVs) of Escherichia coli for tumor treatment, aiming to activate ferroptosis and stimulate the immune responses. Specifically, we functionalize the OMVs by anchoring them with ferrous ions via electrostatic interactions and loading them with the STING agonist-4, followed by tumor-targeting DSPE-PEG-FA decoration, henceforth referred to as OMV/SaFeFA. The anchoring of ferrous ions endows the OMVs with peroxidase-like activity, capable of inducing cellular lipid peroxidation by catalyzing H2O2 to â¢OH. Furthermore, OMV/SaFeFA exhibits pH-responsive release of ferrous ions and the agonist, along with tumor-targeting capabilities, enabling tumor-specific therapy while minimizing side effects. Notably, the concurrent activation of the STING pathway and ferroptosis elicits robust antitumor responses in colon tumor-bearing mouse models, leading to exceptional therapeutic efficacy and prolonged survival. Importantly, no acute toxicity was observed in mice receiving OMV/SaFeFA treatments, underscoring its potential for future tumor therapy and clinical translation.
Asunto(s)
Ferroptosis , Ferroptosis/efectos de los fármacos , Animales , Ratones , Línea Celular Tumoral , Membrana Externa Bacteriana , Escherichia coli , Humanos , Nanopartículas/química , Femenino , Ratones Endogámicos BALB C , Peroxidación de Lípido/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Neoplasias del Colon/tratamiento farmacológico , IonesRESUMEN
Development of ferroptosis-inducible nanoplatforms with high efficiency and specificity is highly needed and challenging in tumor ferrotherapy. Here, we demonstrate highly effective tumor ferrotherapy using iron (II)-based metal-organic framework (FessMOF) nanoparticles, assembled from disulfide bonds and ferrous ions. The as-prepared FessMOF nanoparticles exhibit peroxidase-like activity and pH/glutathione-dependent degradability, which enables tumor-responsive catalytic therapy and glutathione depletion by the thiol/disulfide exchange to suppress glutathione peroxidase 4, respectively. Upon PEGylation and Actinomycin D (ActD) loading, the resulting FessMOF/ActD-PEG nanoplatform induces marked DNA damage and lipid peroxidation. Concurrently, we found that ActD can inhibit Xc- system and elicit ferritinophagy, which further boosts the ferrotherapeutic efficacy of the FessMOF/ActD-PEG. In vivo experiments demonstrate that our fabricated nanoplatform presents excellent biocompatibility and a high tumor inhibition rate of 91.89%.
Asunto(s)
Daño del ADN , Ferroptosis , Hierro , Estructuras Metalorgánicas , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Ferroptosis/efectos de los fármacos , Animales , Humanos , Ratones , Daño del ADN/efectos de los fármacos , Hierro/química , Línea Celular Tumoral , Reparación del ADN/efectos de los fármacos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Ratones Endogámicos BALB C , FemeninoRESUMEN
Cuproptosis is dependent on mitochondrial respiration modulation by targeting lipoylated tricarboxylic acid cycle (TCA) cycle proteins, showing great potential in cancer treatment. However, the specific release of copper ions at mitochondrial is highly needed and still a major challenge to trigger cellular cuproptosis. Herein, a metal-organic framework-based nanoplatform (ZCProP) is designed for mitochondrial-targeted and ATP/pH-responsive Cu2+ and prodigiosin release. The released Cu2+ promotes aggregation of lipoylated protein and loss of Fe-S cluster protein, resulting in cell cuproptosis. In the meanwhile, Cu2+ can concert with prodigiosin to induce mitochondrial dysfunction and DNA damage and enhance cell cuproptosis. Furthermore, this nanoplatform has an ability to deplete glutathione, which not only further promotes cuproptosis but also triggers cell ferroptosis by the suppression of glutathione peroxidase 4, an anti-ferroptosis protein. Collectively, the designed ZCProP nanoplatform can responsively release cargos at mitochondrial and realize a conspicuous therapeutic efficacy through a cuproptosis-mediated concerted effect. Along with its excellent biocompatibility, this nanoplatform may provide a novel therapeutic modality paradigm to boost cancer therapeutic strategies based on cuproptosis.
Asunto(s)
Cobre , Estructuras Metalorgánicas , Mitocondrias , Cobre/química , Cobre/farmacología , Humanos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Animales , Ferroptosis/efectos de los fármacos , Línea Celular Tumoral , RatonesRESUMEN
Phototherapy is a local and precise therapeutic technique for tumor treatment. However, the therapeutic effects of photothermal and photodynamic therapies are inevitably encountered by hypoxia of the tumor microenvironment and heat shock protein induced by hyperthermia, respectively. Herein, we found that mannose, a glucose analog, could reverse tumor hypoxia by inhibiting glycolysis of cancer cells and suppressing the expression of heat shock protein through inhibiting cellular adenosine triphosphate (ATP) generation. Next, we used lipid nanoparticles simultaneously loaded with indocyanine green (ICG) and mannose molecules, named imLipo, for tumor therapy. Both in vitro and in vivo experiments evidenced that the imLipo nanoplatform has significant therapeutic efficacy through synergistic phototherapy under single near-infrared laser irradiation. This work shows that glycolysis inhibition can overcome the challenges of phototherapy. In addition, all three parts (mannose, ICG, and lipid) of imLipo are clinically approved and our designed nanoplatforms have great potential for future tumor treatment.