Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy

• Published in: Science China. Life sciences Vol. 67; no. 7; pp. 1398 - 1412
• Main Authors: Wang, Shuxiang, Cao, Hongmei, Zhao, Cui-Cui, Wang, Qian, Wang, Dianyu, Liu, Jinjian, Yang, Lijun, Liu, Jianfeng
• Format: Journal Article
• Language: English
• Published: Beijing Science China Press 01.07.2024; Springer Nature B.V
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Biomimetics; Cell Line, Tumor; Cell membranes; Cell proliferation; Cell Proliferation - drug effects; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; DNA damage; DNA repair; DNA Repair - drug effects; Glutathione; Humans; Hypoxia; Life Sciences; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Mice; Nanoparticles; Nanoparticles - chemistry; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - radiotherapy; Oxidative stress; Oxidative Stress - drug effects; Oxygen - metabolism; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - therapeutic use; Radiation therapy; Radiation Tolerance - drug effects; Radiation-Sensitizing Agents - pharmacology; Radioresistance; Radiosensitization; Research Paper; Tumor cells; Tumors; biomimetic nanosystem; oxidative stress amplification; glutathione consumption; DNA damage fixation; hypoxia alleviation; radiosensitization
• ISSN: 1674-7305; 1869-1889; 1869-1889
• DOI: 10.1007/s11427-023-2528-5

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 (O 2 ) 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 O 2 and Pt(IV). O 2 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.