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Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy

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Abstract

Tumor cells establish a robust self-defense system characterized by hypoxia, antioxidant overexpression, DNA damage repair, and so forth to resist radiotherapy. Targeting one of these features is insufficient to overcome radioresistance due to the feedback mechanisms initiated by tumor cells under radiotherapy. Therefore, we herein developed an engineering biomimetic nanosystem (M@HHPt) masked with tumor cell membranes and loaded with a hybridized protein-based nanoparticle carrying oxygens (O2) and cisplatin prodrugs (Pt(IV)) to target multiple tumor radioresistance hallmarks for enhanced radiotherapy. After administration, M@HHPt actively targeted and smoothly accumulated in tumor cells by virtue of its innate homing abilities to realize efficient co-delivery of O2 and Pt(IV). O2 introduction induced hypoxia alleviation cooperated with Pt(IV) reduction caused glutathione consumption greatly amplified radiotherapy-ignited cellular oxidative stress. Moreover, the released cisplatin effectively hindered DNA damage repair by crosslinking with radiotherapy-produced DNA fragments. Consequently, M@HHPt-sensitized radiotherapy significantly suppressed the proliferation of lung cancer H1975 cells with an extremely high sensitizer enhancement ratio of 1.91 and the progression of H1975 tumor models with an excellent tumor inhibition rate of 94.7%. Overall, this work provided a feasible strategy for tumor radiosensitization by overcoming multiple radioresistance mechanisms.

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Acknowledgement

This work was supported by the National Science Fund for Distinguished Young Scholars of China (82225026), the National Natural Science Foundation of China (82172082), and CAMS Innovation Fund for Medical Sciences (2021-I2M-1-042, 2023-I2M-QJ-016).

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  1. Contributed equally to this work

Authors and Affiliations

  1. State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China

    Shuxiang Wang, Hongmei Cao, Qian Wang, Dianyu Wang, Jinjian Liu, Lijun Yang & Jianfeng Liu

  2. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy (Tianjin), Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China

    Cui-Cui Zhao

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  1. Shuxiang Wang
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Correspondence to Lijun Yang or Jianfeng Liu.

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Wang, S., Cao, H., Zhao, CC. et al. Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2528-5

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