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Metal ions-anchored bacterial outer membrane vesicles for enhanced ferroptosis induction and immune stimulation in targeted antitumor therapy.

ABSTRACT: 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 ^•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.

SUBMITTER: Sun Y

PROVIDER: S-EPMC11311927 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Metal ions-anchored bacterial outer membrane vesicles for enhanced ferroptosis induction and immune stimulation in targeted antitumor therapy.

Sun Ying Y Ma Yan-Yan YY Shangguan Shijie S Ruan Yihang Y Bai Tingjie T Xue Panpan P Zhuang Huilan H Cao Wenyu W Cai Huimei H Tang Enqi E Wu Zhou Z Yang Mingzhen M Zeng Yixin Y Sun Juan J Fan Yong Y Zeng Xuemei X Yan Shuangqian S

Journal of nanobiotechnology 20240809 1

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 functiona ...[more]

PMID: 39123234

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Project description:PurposeSide effects related to radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in directly irradiated cells. However, several studies have reported over the years of radiation-induced non-targeted/ abscopal effects in vivo that challenge this paradigm. There is evidence that Cyclooxygenase-2 (COX2) plays an important role in modulating non-targeted effects, including DNA damages in vitro and mutagenesis in vivo. While most reports on radiation-induced non-targeted response utilize x-rays, there is little information available for heavy ions.Methods and materialsAdult female transgenic gpt delta mice were exposed to an equitoxic dose of either carbon or argon particles using the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS) in Japan. The mice were stratified into 4 groups of 5 animals each: Control; animals irradiated under full shielding (Sham-irradiated); animals receiving whole body irradiation (WBIR); and animals receiving partial body irradiation (PBIR) to the lower abdomen with a 1 x 1 cm2 field. The doses used in the carbon ion group (4.5 Gy) and in argon particle group (1.5 Gy) have a relative biological effectiveness equivalent to a 5 Gy dose of x-rays. 24 hours after irradiation, breast tissues in and out of the irradiated field were harvested for analysis. Induction of COX2, 8-hydroxydeoxyguanosine (8-OHdG), phosphorylated histone H2AX (γ-H2AX), and apoptosis-related cysteine protease-3 (Caspase-3) antibodies were examined in the four categories of breast tissues using immunohistochemical techniques. Analysis was performed by measuring the intensity of more than 20 individual microscopic fields and comparing the relative fold difference.ResultsIn the carbon ion group, the relative fold increase in COX2 expression was 1.01 in sham-irradiated group (p > 0.05), 3.07 in PBIR (p < 0.05) and 2.50 in WBIR (p < 0.05), respectively, when compared with controls. The relative fold increase in 8-OHdG expression was 1.29 in sham-irradiated (p > 0.05), 11.31 in PBIR (p < 0.05) and 11.79 in WBIR (p < 0.05), respectively, when compared with controls. A similar increase in γ-H2AX expression was found in that, compared to controls, the increase was 1.41 fold in sham-irradiated (p > 0.05), 8.41 in PBIR (p < 0.05) and 10.59 in WBIR (p < 0.05). Results for the argon particle therapy group showed a similar magnitude of changes in the various biological endpoints examined. There was no statistical significance observed in Caspase-3 expression among the 4 groups.ConclusionsOur data show that both carbon and argon ions induced non-targeted, out of field induction of COX2 and DNA damages in breast tissues. These effects may pose new challenges to evaluate the risks associated with radiation exposure and understanding radiation-induced side effects.

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Dataset Information

Metal ions-anchored bacterial outer membrane vesicles for enhanced ferroptosis induction and immune stimulation in targeted antitumor therapy.

Publications

Metal ions-anchored bacterial outer membrane vesicles for enhanced ferroptosis induction and immune stimulation in targeted antitumor therapy.

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