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Mutually reinforcing nanofactory mimicking controllable “cluster bomb” for synergistic diagnosis and treatment of hypoxic cancer

一种智能纳米酶工厂作为诊疗纳米平台用于协同癌症治疗

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Abstract

Multimodal therapy presents one of the most promising strategies for combining multiple therapies to treat the usually complex and insidious tumor tissue. Although multifunctional nanomaterials have been designed for the construction of multimodal therapies, the generally existing inadequate coordination among components might result in low synergistic therapeutic effects and prevent the realization of their full clinical potential. Herein, inspired by the controllable “cluster bomb” model, we designed an intelligent, biocompatible, and multifunctional nanofactory system (PDA@GOx@MnO2-PEG) that encapsulates a variety of nanoagents to achieve high destruction efficiency against tumor. The stimulus-responsive outer MnO2 acts as the shell of “bomb” triggering the cascade catalytic reaction and forms a self-sustainable ring catalytic chain with glucose oxidase (GOx). Polydopamine (PDA) as a substrate with excellent protein carrying capacity achieves high GOx loading. Meanwhile, its efficient photothermal conversion efficiency exhibits the potential of low-temperature (∼45°C) to further enhance GOx enzymatic activity. Notably, the internal GOx is like a “sub-bomb” that is released in a controlled manner to increase the accumulation at tumor hypoxic sites, and gives full play to its glucose consumption capacity for starvation therapy under the help of sufficient oxygen and low hyperthermia. In this system, various nanoagents cooperate and advance layer by layer to fully exploit their power, forming a self-sufficient nanofactory model, and achieving excellent low-temperature photothermal-starvation synergistic therapy through a synergistic strategy. Moreover, the nanocomposite exhibits trimodal imaging capability for sensitive diagnosis and real-time monitoring of therapy. This study provides new insights for designing biocompatible and intelligent theranostic nanoplatforms to maximize the multi-modal therapeutic effect in precision medicine.

摘要

多模态疗法是结合多种疗法治疗通常复杂而隐蔽的肿瘤组织的最有希望的策略之一. 尽管多功能纳米材料已被设计用于构建多模态疗法, 但普遍存在的各组成部分之间的不充分协调可能导致协同治疗效果不佳, 并妨碍其充分实现临床潜力. 在此, 受可控“集束炸弹”模型的启发, 我们设计了一种智能、 生物相容、 多功能的纳米工厂系统(PDA@GOx@MnO2-PEG), 它封装了多种纳米试剂, 以达到对肿瘤组织的高破坏效率. 刺激反应性的外层二氧化锰作为“炸弹”的外壳可触发级联催化反应, 并与GOx形成一个自给自足的环形催化链. PDA作为一种具有良好蛋白质携带能力的基质, 实现了高的GOx负载. 同时, 其高效的光热转换效率显示了低温(~45°C)进一步提高GOx酶活性的潜力. 值得注意的是, 内部的GOx就像一个“子炸弹”, 通过控制释放来增加肿瘤缺氧部位的积累, 并在充足的氧气和低热度的帮助下充分发挥其葡萄糖消耗能力进行饥饿治疗. 在这个体系中, 各种纳米试剂相互配合, 层层推进, 充分发挥其威力, 形成了一个自给自足的纳米工厂模型, 通过协同策略实现了良好的低温光热-饥饿协同治疗. 此外, 该纳米复合材料表现出三态成像能力, 可用于敏感诊断和实时监控治疗. 这项研究为设计生物相容性和智能治疗纳米平台提供了新的见解, 使精准医疗中的多模式治疗效果最大化.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (21705117, 21904095, 22001193, and 22174110), the Elite Scholar Program of Tianjin University (2019XRG-0065), the Program of Tianjin Science and Technology Major Project and Engineering (19ZXYXSY00090), the Program for Chang Jiang Scholars and Innovative Research Team, Ministry of Education, China (IRT-16R61), and the Special Fund Project for the Central Government to Guide Local Science and Technology Development (2020).

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Authors and Affiliations

  1. Key Laboratory of Bioelectrochemistry and Environmental Analysis of Gansu Province, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, 730070, China

    Fangfang Dai  (戴芳芳) & Xiaoquan Lu  (卢小泉)

  2. Tianjin Key Laboratory of Molecular Optoelectronic Department of Chemistry, School of Science, Tianjin University, Tianjin, 300072, China

    Fangfang Dai  (戴芳芳), Mingsen Xie  (谢明森), Peiyao Du  (杜佩瑶), Zhen Zhang  (张振) & Xiaoquan Lu  (卢小泉)

  3. School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China

    Meiling Chen  (陈美玲)

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  1. Fangfang Dai  (戴芳芳)
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  2. Mingsen Xie  (谢明森)
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  3. Peiyao Du  (杜佩瑶)
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  4. Zhen Zhang  (张振)
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  5. Meiling Chen  (陈美玲)
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  6. Xiaoquan Lu  (卢小泉)
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Contributions

Author contributions Lu X and Zhang Z initiated and supervised the project. Chen M performed the cell culture studies. Dai F designed the experiments, collected the data and wrote this paper. Xie M analyzed the experimental data. Du P commented on the manuscript. All authors contributed to the general discussion.

Corresponding authors

Correspondence to Zhen Zhang  (张振), Meiling Chen  (陈美玲) or Xiaoquan Lu  (卢小泉).

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Conflict of interest The authors declare that they have no conflict of interest.

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Supplementary information Experimental details and supporting data are available in the online version of the paper.

Fangfang Dai received her BSc degree from the College of Science, Tianjin Normal University. She obtained her MSc and PhD degrees at Tianjin University under the supervision of Prof. Lu. Her research focuses on the design and fabrication of functional nanomaterials and related applications.

Zhen Zhang obtained his PhD degree from the Institute of Chemistry, Chinese Academy of Sciences in 2017, after which he joined Tianjin University as a lecturer in 2017. He was a visiting scholar in the laboratory of Prof. Yadong Yin at the University of California (Riverside) in 2019–2020. His scientific interest is mainly focused on the design and fabrication of functional nanomaterials and related applications.

Meiling Chen graduated from Liaoning Normal University majoring in chemistry in 2008. She received her PhD degree in analytical chemistry from Northeastern University in 2013. Her scientific interest is carbon nanomaterials and related analytical applications in life sciences.

Xiaoquan Lu received his BSc and MSc degrees from the Department of Chemistry, Northwest Normal University in 1994, and his PhD degree from Sun Yat-sen University in 1997. He was a visiting scholar at Changchun Institute of Applied Chemistry, Chinese Academy of Sciences in 2001. His research interests are bioelectrochemistry, visual sensing, and new energy development.

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Mutually reinforcing nanofactory mimicking controllable “cluster bomb” for synergistic diagnosis and treatment of hypoxic cancer

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Dai, F., Xie, M., Du, P. et al. Mutually reinforcing nanofactory mimicking controllable “cluster bomb” for synergistic diagnosis and treatment of hypoxic cancer. Sci. China Mater. 66, 4499–4511 (2023). https://doi.org/10.1007/s40843-023-2583-5

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