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. 2024 Sep 26:29:101275.
doi: 10.1016/j.mtbio.2024.101275. eCollection 2024 Dec.

Cancer cell membrane-coated siRNA-Decorated Au/MnO2 nanosensitizers for synergistically enhanced radio-immunotherapy of breast cancer

Diyu Wang  1   2 , Subin Lin  1 , Tuanwei Li  2 , Xiaohu Yang  2 , Xiang Zhong  1 , Qian Chen  2 , Guoqin Jiang  1 , Chunyan Li  2   3
Affiliations

Cancer cell membrane-coated siRNA-Decorated Au/MnO2 nanosensitizers for synergistically enhanced radio-immunotherapy of breast cancer

Diyu Wang et al. Mater Today Bio. .

Abstract

Radiotherapy plays a critical role in the clinical treatment of breast cancer. However, the efficacy of traditional X-ray radiotherapy is greatly limited by its low tumor specificity and treatment tolerance mediated by the tumor microenvironment. Herein, we proposed a novel nano-radiotherapy sensitization strategy to design and construct a cancer cell membrane-coated siRNA-decorated Au/MnO2 nanosensitizer (R&F@Au/MnO2-CM) to synergistically enhance radio-immunotherapy for breast cancer. In the integrated nanosensitizer, the cancer cell membrane (CM) derived from 4T1 breast cancer cells is utilized for targeted functionality, while Au/MnO2 is designed to improve X-ray absorption and alleviate tumor hypoxia. Additionally, PD-L1 siRNA (R) is used to downregulate PD-L1 expression in tumor cells. In an in situ mouse model of 4T1 breast cancer, R&F@Au/MnO2-CM demonstrated accurate tumor identification via CM-mediated homologous targeting after intravenous injection, which was monitored in real-time through NIR-II fluorescence imaging of NIR-935 (F). Subsequently, the radiotherapy sensitivity was achieved due to the strong radiation absorption properties and oxygen generation through catalysis of Au/MnO2 upon X-ray irradiation. Furthermore, the immunosuppressive microenvironment of the tumor is improved by downregulating PD-L1, enhancing synergistic anti-tumor effect. Our findings demonstrate a promising approach for tumor treatment by combining targeted enhanced radiotherapy with immune activation.

Keywords: NIR-II fluorescence; Nanosensitizer; Radiotherapy; Tumor therapy.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Scheme 1
Scheme 1
Schematic illustration of R&F@Au/MnO2-CM for cancer-cell-biomimetic nano-radiotherapy sensitizer for synergistically enhanced radio-immunotherapy of breast cancer.
Fig. 1
Fig. 1
Characterization of R&F@Au/MnO-CM. (a) TEM images of AuNPs, Au/MnO2 and R&F@Au/MnO2-CM. (b) SDS-PAGE protein analysis. Samples were stained with bromophenol blue. (c, d) Hydrodynamic diameters and zeta potentials of Au/MnO2, R@Au/MnO2-CM and R&F@Au/MnO2-CM (n = 3). (e) Absorbance of Au/MnO2, R@Au/MnO2, R&F@Au/MnO2-CM and emission spectrum of R&F@Au/MnO2-CM.
Fig. 2
Fig. 2
In vitro cellular internalization. (a) Fluorescence images of cellular uptake of R&F@Au/MnO2-CM in different cell lines for 1 h. (b) Quantification analysis for the homologous targeting efficiency. (c) Fluorescence imaging of 4T1 cells after incubating with R&F@Au/MnO2-CM for different time. (d) Flow cytometry analysis for the transfection efficiency on 4T1 cells at 1 h, 2 h and 4 h after different treatments. (e) Quantification analysis of FCM analysis. Data are given as mean ± SD (n = 3). ∗p < 0.05, ∗∗p < 0.01.
Fig. 3
Fig. 3
In vitro radio-sensitization and PD-L1 expression in 4T1 cells after radiotherapy (RT). (a) CLSM images of γ-H2AX foci in 4T1 cells with different treatments. (b) Quantification analysis of γ-H2AX foci. (c) Model for PD-L1 upregulation in response to DSBs. DSBs active ATM, a central signal transducer, after RT. ATM then actives ATR/Chk1. The signal conducts to STAT-IRF1 pathway. Eventually, the expression of PD-L1 is upregulated to DSB [21]. (d) Western blot of PD-L1 expression in 4T1 cells was examined before irradiation, 24 h and 48 h after RT. (e) Quantitative analysis of the western blot. Data are given as mean ± SD (n = 3). ∗p < 0.05, ∗∗p < 0.01.
Fig. 4
Fig. 4
In vivo homologous targeting and anti-tumor efficiency. (a) Schematic illustration of anti-tumor schedule. (b) NIR-II fluorescence images of R&F@Au/MnO2-CM and R&F@Au/MnO2-CMEMT6 at designed time intervals. (c) Quantitative analysis of TBR at tumor sites at different time. (d) The tumor growth curves. (e) Imaging of the tumors collected from mice on day 15 of treatment (n = 5). (f) The overall survival time of tumor-bearing mice (n = 7). (g) Western blot analysis of PD-L1 expression in tumor tissue and quantitative analysis of the western blot (n = 3). Data was given as mean ± SD. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
Fig. 5
Fig. 5
In vivo anti-tumor efficiency. (a) Histopathological analysis of tumor tissues, including H&E, IHC of CD31, Ki67 and PD-L1. Quantification analysis of the positive area percentage of (b) CD31, (c) Ki67 and (d) PD-L1. Red arrows indicate capillaries. Data was given as mean ± SD. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.
Fig. 6
Fig. 6
In vivo immune mechanism study. (a) Representative immunofluorescence images of tumor slices stained with DAPI (blue), CD8+ T cells antibodies (red). (b) and (c) representative FCM plots and the corresponding quantitative statistics of CD3+ CD8+ T cells (gated on CD45+/CD11b− cells) in tumor tissue (n = 6). (d) TNF-α and (e) IFN-γ by ELISA kits. Mean ± SD (n = 4). ∗p < 0.05, ∗∗p < 0.01.
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