Skip to main content
SpringerLink
Log in

Reprogramming tumor-immune cell communication with a radiosensitive nanoregulator for immunotherapy

放射敏感的纳米调节剂重新编程肿瘤-免疫细胞通讯用于免疫治疗

  • Articles
  • Published:
Science China Materials Aims and scope Submit manuscript

Abstract

Modulating tumor-associated macrophages from tumor-promoting M2 to tumoricidal M1 phenotype is promising for anti-tumor immunotherapy but remains challenging, especially in a controllable manner. Herein, we report a radiosensitive nanoregulator (AuDAP) for activatable immunotherapy. AuDAP can simultaneously recognize and bind M2 macrophages with tumor cells by polyvalent interactions. Under low-dose medical X-ray irradiation, the nanoregulator could generate reactive oxygen species (ROS) to activate the nuclear factor kappa-B (NF-κB) signaling pathway to repolarize M2 macrophages into M1 phenotype, thereby activating the immune function of macrophages in situ. A series of in vitro and in vivo experiments demonstrated the cell communication remodeling and immunotherapy activation effects of AuDAP. As a result, AuDAP + X-ray inhibited the growth of tumors and effectively prevented their metastasis during a long period of observation. This nanoregulator may serve as a promising nanomedicine for precise tumor therapy, and this work offers new insights for activatable immunotherapy.

摘要

目前, 将肿瘤相关巨噬细胞从促肿瘤生长的M2表型调节为抑制肿瘤生长的M1表型已成为一种有前途的肿瘤免疫治疗策略, 但仍然具有挑战性, 而且以可控的方式实现显得尤为困难. 在此, 我们报道了一种用于可时空激活免疫反应的放射敏感型纳米调节剂(AuDAP). AuDAP可通过多价相互作用同时识别和结合M2巨噬细胞与肿瘤细胞. 在低剂量医用X射线照射下, 纳米调节剂可介导产生大量活性氧(ROS), 激活NF-κB信号通路, 使M2型巨噬细胞复极化为M1型, 从而原位激活巨噬细胞的免疫功能. 一系列体外和体内实验结果表明, 纳米调节剂可以有效重塑肿瘤细胞和巨噬细胞之间的通讯, 并特异性地激活抗肿瘤免疫治疗. 通过长时间观察发现, 治疗组小鼠的原位肿瘤被明显抑制且未观察到肺部转移瘤的形成. 该纳米调节剂可作为一种有潜力的纳米药物用于精确的肿瘤治疗, 并能为可控的免疫治疗提供新的见解.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Goldberg MS. Improving cancer immunotherapy through nanotechnology. Nat Rev Cancer, 2019, 19: 587–602.

    Article  CAS  Google Scholar 

  2. Singh AK, McGuirk JP. CAR T cells: Continuation in a revolution of immunotherapy. Lancet Oncol, 2020, 21: e168–e178.

    Article  CAS  Google Scholar 

  3. Chao Y, Xu L, Liang C, et al. Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumour responses. Nat Biomed Eng, 2018, 2: 611–621

    Article  CAS  Google Scholar 

  4. Li J, Luo Y, Pu K. Electromagnetic nanomedicines for combinational cancer immunotherapy. Angew Chem Int Ed, 2021, 60: 12682–12705.

    Article  CAS  Google Scholar 

  5. Yang Y, Xu J, Sun Y, et al. Aptamer-based logic computing reaction on living cells to enable non-antibody immune checkpoint blockade therapy. J Am Chem Soc, 2021, 143: 8391–8401

    Article  CAS  Google Scholar 

  6. Ni K, Luo T, Nash GT, et al. Nanoscale metal-organic frameworks for cancer immunotherapy. Acc Chem Res, 2020, 53: 1739–1748

    Article  CAS  Google Scholar 

  7. Hu Q, Li H, Wang L, et al. DNA nanotechnology-enabled drug delivery systems. Chem Rev, 2019, 119: 6459–6506

    Article  CAS  Google Scholar 

  8. Zhang P, Zhai Y, Cai Y, et al. Nanomedicine-based immunotherapy for the treatment of cancer metastasis. Adv Mater, 2019, 31: 1904156

    Article  CAS  Google Scholar 

  9. Fan Z, Liu H, Xue Y, et al. Reversing cold tumors to hot: An immunoadjuvant-functionalized metal-organic framework for multimodal imaging-guided synergistic photo-immunotherapy. Bioactive Mater, 2021, 6: 312–325

    Article  CAS  Google Scholar 

  10. Ruan H, Hu Q, Wen D, et al. A dual-bioresponsive drug-delivery depot for combination of epigenetic modulation and immune checkpoint blockade. Adv Mater, 2019, 31: 1806957

    Article  Google Scholar 

  11. Qin H, Zhao R, Qin Y, et al. Development of a cancer vaccine using in vivo click-chemistry-mediated active lymph node accumulation for improved immunotherapy. Adv Mater, 2021, 33: 2006007

    Article  CAS  Google Scholar 

  12. Gong N, Zhang Y, Teng X, et al. Proton-driven transformable nanovaccine for cancer immunotherapy. Nat Nanotechnol, 2020, 15: 1053–1064

    Article  CAS  Google Scholar 

  13. Zhang D, Zheng Y, Lin Z, et al. Equipping natural killer cells with specific targeting and checkpoint blocking aptamers for enhanced adoptive immunotherapy in solid tumors. Angew Chem Int Ed, 2020, 59: 12022–12028

    Article  CAS  Google Scholar 

  14. Zhang Y, Liao Y, Tang Q, et al. Biomimetic nanoemulsion for synergistic photodynamic-immunotherapy against hypoxic breast tumor. Angew Chem Int Ed, 2021, 60: 10647–10653

    Article  CAS  Google Scholar 

  15. Spear TT, Nagato K, Nishimura MI. Strategies to genetically engineer T cells for cancer immunotherapy. Cancer Immunol Immunother, 2016, 65: 631–649.

    Article  CAS  Google Scholar 

  16. Wang W, Jin Y, Liu X, et al. Endogenous stimuli-activatable nano-medicine for immune theranostics for cancer. Adv Funct Mater, 2021, 31: 2100386

    Article  CAS  Google Scholar 

  17. Huang B, Abraham WD, Zheng Y, et al. Active targeting of chemotherapy to disseminated tumors using nanoparticle-carrying T cells. Sci Transl Med, 2015, 7: 291ra94

    Article  Google Scholar 

  18. Phuengkham H, Ren L, Shin IW, et al. Nanoengineered immune niches for reprogramming the immunosuppressive tumor microenvironment and enhancing cancer immunotherapy. Adv Mater, 2019, 31: 1803322

    Article  Google Scholar 

  19. Goswami KK, Ghosh T, Ghosh S, et al. Tumor promoting role of antitumor macrophages in tumor microenvironment. Cell Immunol, 2017, 316: 1–10

    Article  CAS  Google Scholar 

  20. Chen Y, Gao P, Pan W, et al. Polyvalent spherical aptamer engineered macrophages: X-ray-actuated phenotypic transformation for tumor immunotherapy. Chem Sci, 2021, 12: 13817–13824

    Article  CAS  Google Scholar 

  21. Ovais M, Guo M, Chen C. Tailoring nanomaterials for targeting tumor-associated macrophages. Adv Mater, 2019, 31: 1808303.

    Article  Google Scholar 

  22. Zhou J, Liu W, Zhao X, et al. Natural melanin/alginate hydrogels achieve cardiac repair through ROS scavenging and macrophage polarization. Adv Sci, 2021, 8: 2100505

    Article  CAS  Google Scholar 

  23. Liu Y, Balachandran YL, Li Z, et al. Two dimensional nanosheets as immunoregulator improve HIV vaccine efficacy. Chem Sci, 2022, 13: 178–187

    Article  Google Scholar 

  24. Chen M, Miao Y, Qian K, et al. Detachable liposomes combined immunochemotherapy for enhanced triple-negative breast cancer treatment through reprogramming of tumor-associated macrophages. Nano Lett, 2021, 21: 6031–6041

    Article  CAS  Google Scholar 

  25. Li J, Jiang X, Li H, et al. Tailoring materials for modulation of macrophage fate. Adv Mater, 2021, 33: 2004172

    Article  CAS  Google Scholar 

  26. Qiu N, Wang G, Wang J, et al. Tumor-associated macrophage and tumor-cell dually transfecting polyplexes for efficient interleukin-12 cancer gene therapy. Adv Mater, 2021, 33: 2006189

    Article  CAS  Google Scholar 

  27. Rao L, Wu L, Liu Z, et al. Hybrid cellular membrane nanovesicles amplify macrophage immune responses against cancer recurrence and metastasis. Nat Commun, 2020, 11: 4909

    Article  Google Scholar 

  28. Huang W, He L, Zhang Z, et al. Shape-controllable tellurium-driven heterostructures with activated robust immunomodulatory potential for highly efficient radiophotothermal therapy of colon cancer. ACS Nano, 2021, 15: 20225–20241

    Article  CAS  Google Scholar 

  29. Ma S, Song W, Xu Y, et al. A ROS-responsive aspirin polymeric pro-drug for modulation of tumor microenvironment and cancer immunotherapy. CCS Chem, 2020, 2: 390–400.

    Article  CAS  Google Scholar 

  30. Zhao YD, Muhetaerjiang M, An HW, et al. Nanomedicine enables spatiotemporally regulating macrophage-based cancer immunotherapy. Biomaterials, 2021, 268: 120552

    Article  CAS  Google Scholar 

  31. Luan M, Shi M, Pan W, et al. A gold-selenium-bonded nanoprobe for real-time in situ imaging of the upstream and downstream relationship between uPA and MMP-9 in cancer cells. Chem Commun, 2019, 55: 5817–5820

    Article  CAS  Google Scholar 

  32. Li N, Chang C, Pan W, et al. A multicolor nanoprobe for detection and imaging of tumor-related mRNAs in living cells. Angew Chem Int Ed, 2012, 51: 7426–7430

    Article  CAS  Google Scholar 

  33. Zheng H, Shang GQ, Yang SY, et al. Fluorogenic and chromogenic rhodamine spirolactam based probe for nitric oxide by spiro ring opening reaction. Org Lett, 2008, 10: 2357–2360

    Article  CAS  Google Scholar 

  34. Dou Y, Guo Y, Li X, et al. Size-tuning ionization to optimize gold nanoparticles for simultaneous enhanced CT imaging and radiotherapy. ACS Nano, 2016, 10: 2536–2548

    Article  CAS  Google Scholar 

  35. Chen X, Song J, Chen X, et al. X-ray-activated nanosystems for theranostic applications. Chem Soc Rev, 2019, 48: 3073–3101

    Article  CAS  Google Scholar 

  36. Chen Y, Gao P, Wu T, et al. Organelle-localized radiosensitizers. Chem Commun, 2020, 56: 10621–10630

    Article  CAS  Google Scholar 

  37. Gao P, Liu B, Pan W, et al. A spherical nucleic acid probe based on the Au−Se bond. Anal Chem, 2020, 92: 8459–8463

    Article  CAS  Google Scholar 

  38. Liu B, Liu J. Freezing directed construction of bio/nano interfaces: Reagentless conjugation, denser spherical nucleic acids, and better nanoflares. J Am Chem Soc, 2017, 139: 9471–9474.

    Article  CAS  Google Scholar 

  39. Zhao Y, Zuo X, Li Q, et al. Nucleic acids analysis. Sci China Chem, 2020, 64: 171–203

    Article  Google Scholar 

  40. Meng HM, Liu H, Kuai H, et al. Aptamer-integrated DNA nanostructures for biosensing, bioimaging and cancer therapy. Chem Soc Rev, 2016, 45: 2583–2602

    Article  CAS  Google Scholar 

  41. Xiao H, Guo Y, Li B, et al. M2-like tumor-associated macrophage-targeted codelivery of STAT6 inhibitor and IKKβ siRNA induces M2-to-M1 repolarization for cancer immunotherapy with low immune side effects. ACS Cent Sci, 2020, 6: 1208–1222

    Article  CAS  Google Scholar 

  42. Cao F, Zhang Y, Sun Y, et al. Ultrasmall nanozymes isolated within porous carbonaceous frameworks for synergistic cancer therapy: Enhanced oxidative damage and reduced energy supply. Chem Mater, 2018, 30: 7831–7839

    Article  CAS  Google Scholar 

  43. Ding B, Shao S, Yu C, et al. Large-pore mesoporous-silica-coated up-conversion nanoparticles as multifunctional immunoadjuvants with ultrahigh photosensitizer and antigen loading efficiency for improved cancer photodynamic immunotherapy. Adv Mater, 2018, 30: 1802479

    Article  Google Scholar 

  44. Wang X, Sun M, Qu A, et al. Improved reactive oxygen species generation by chiral Co3O4 supraparticles under electromagnetic fields. Angew Chem Int Ed, 2021, 60: 18240–18246

    Article  CAS  Google Scholar 

  45. Shi C, Liu T, Guo Z, et al. Reprogramming tumor-associated macrophages by nanoparticle-based reactive oxygen species photogeneration. Nano Lett, 2018, 18: 7330–7342

    Article  CAS  Google Scholar 

  46. Li Y, Teng X, Yang C, et al. Ultrasound controlled anti-inflammatory polarization of platelet decorated microglia for targeted ischemic stroke therapy. Angew Chem Int Ed, 2021, 60: 5083–5090

    Article  CAS  Google Scholar 

  47. Rao L, Zhao SK, Wen C, et al. Activating macrophage-mediated cancer immunotherapy by genetically edited nanoparticles. Adv Mater, 2020, 32: 2004853

    Article  CAS  Google Scholar 

  48. Yang Y, Sun X, Xu J, et al. Circular bispecific aptamer-mediated artificial intercellular recognition for targeted T cell immunotherapy. ACS Nano, 2020, 14: 9562–9571

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21927811 and 21874086) and the Youth Innovation Science and Technology Program of Higher Education Institution of Shandong Province (2019KJC022).

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan, 250014, China

    Yuanyuan Chen  (陈园园), Shujie Liu  (刘淑杰), Peng Gao  (高鹏), Wei Pan  (潘伟), Mingwan Shi  (石明婉), Na Li  (李娜) & Bo Tang  (唐波)

  2. Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China

    Jianbo Wang  (王建波)

Authors
  1. Yuanyuan Chen  (陈园园)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shujie Liu  (刘淑杰)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng Gao  (高鹏)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Pan  (潘伟)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mingwan Shi  (石明婉)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jianbo Wang  (王建波)
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Na Li  (李娜)
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bo Tang  (唐波)
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Chen Y, Liu S, Gao P, Wang J, Li N, and Tang B designed and engineered the samples; Chen Y, Gao P, Wang J, Li N, and Tang B conceived the post-fabrication tuning of random modes; Chen Y, Liu S, and Shi M performed the experiments; Chen Y, Liu S, and Gao P wrote the paper with support from Pan W, Li N, and Tang B. All authors contributed to the general discussion.

Corresponding authors

Correspondence to Jianbo Wang  (王建波), Na Li  (李娜) or Bo Tang  (唐波).

Additional information

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary information

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

Yuanyuan Chen is currently pursuing a PhD degree at the College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University. Her current research interest is the design and synthesis of functional nanomaterials for tumor radiotherapy

Bo Tang obtained his PhD degree in analytical chemistry in 1994 from Nankai University. Then he joined the College of Chemistry, Chemical Engineering and Materials Science as a full professor at Shandong Normal University. His current research interests include the development of molecular and nano probes for analytical and biomedical applications, solar energy chemical transformation and storage, and clean synthesis of chemicals

Supplementary Materials

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Y., Liu, S., Gao, P. et al. Reprogramming tumor-immune cell communication with a radiosensitive nanoregulator for immunotherapy. Sci. China Mater. 66, 352–362 (2023). https://doi.org/10.1007/s40843-022-2140-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40843-022-2140-7

Keywords

Search

Navigation