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Immunomodulatory hybrid bio-nanovesicle for self-promoted photodynamic therapy

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Abstract

Thylakoid (Tk) membranes are of unique superiority in photodynamic therapy (PDT) because they not only carry abundant chlorophylls containing photosensitizer porphyrin but also can produce O2. However, the current therapeutic performance of Tk is dramatically limited because of their poor tumor targeting and inefficient O2 production. Here, we report an immunomodulatory bio-nanovesicle of Tk membranes fused with M1 macrophage-derived extracellular vesicles (M1 EV) for efficient PDT of tumors. The hybrid nanovesicle Tk@M1 was prepared by squeezing the Tk membranes of spinach with M1 EV. The systemic study confirmed that Tk@M1 can not only actively accumulate in tumors but also effectively regulate the inactive immune microenvironment of tumors. Such activated “hot” tumors significantly enhance the PDT efficacy of Tk@M1 attributed to the increased O2 from catalase catalyzed decomposition of augmented H2O2, providing a novel idea about constructing natural systems for effective tumor treatment.

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References

  1. Karges, J.; Kuang, S.; Maschietto, F.; Blacque, O.; Ciofini, I.; Chao, H.; Gasser, G. Rationally designed ruthenium complexes for 1- and 2-photon photodynamic therapy. Nat. Commun. 2020, 11, 3262.

    Article  CAS  Google Scholar 

  2. Van Straten, D.; Mashayekhi, V.; De Bruijn, H. S.; Oliveira, S.; Robinson, D. J. Oncologic photodynamic therapy: Basic principles, current clinical status, and future directions. Cancers 2017, 9, 19.

    Article  Google Scholar 

  3. Yang, Y. M.; Hu, Y.; Wang, H. J. Targeting antitumor immune response for enhancing the efficacy of photodynamic therapy of cancer: Recent advances and future perspectives. Oxid. Med. Cell. Longev. 2016, 2016, 5274084.

    Article  Google Scholar 

  4. Li, X. S.; Lovell, J. F.; Yoon, J.; Chen, X. Y. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat. Rev. Clin. Oncol. 2020, 17, 657–674.

    Article  Google Scholar 

  5. Liu, B. Q.; Jiao, J.; Xu, W.; Zhang, M. Y.; Cui, P.; Guo, Z. Q.; Deng, Y. B.; Chen, H. B.; Sun, W. F. Highly efficient far-red/NIR-absorbing neutral Ir(III) complex micelles for potent photodynamic/photothermal therapy. Adv. Mater. 2021, 33, 2100795.

    Article  CAS  Google Scholar 

  6. Zhou, Z. J.; Song, J. B.; Nie, L. M.; Chen, X. Y. Reactive oxygen species generating systems meeting challenges of photodynamic cancer therapy. Chem. Soc. Rev. 2016, 45, 6597–6626.

    Article  CAS  Google Scholar 

  7. O’Connor, A. E.; Gallagher, W. M.; Byrne, A. T. Porphyrin and nonporphyrin photosensitizers in oncology: Preclinical and clinical advances in photodynamic therapy. Photochem. Photobiol. 2009, 85, 1053–1074.

    Article  Google Scholar 

  8. Dai, X. X.; Du, T.; Han, K. Engineering nanoparticles for optimized photodynamic therapy. ACS Biomater. Sci. Eng. 2019, 5, 6342–6354.

    Article  CAS  Google Scholar 

  9. Chen, J. M.; Fan, T. J.; Xie, Z. J.; Zeng, Q. Q.; Xue, P.; Zheng, T. T.; Chen, Y.; Luo, X. L.; Zhang, H. Advances in nanomaterials for photodynamic therapy applications: Status and challenges. Biomaterials 2020, 237, 119827.

    Article  CAS  Google Scholar 

  10. Liu, Z. Y.; Cao, T. Y.; Xue, Y. D.; Li, M. T.; Wu, M. S.; Engle, J. W.; He, Q. J.; Cai, W. B.; Lan, M. B.; Zhang, W. A. Self-amplified photodynamic therapy through the 1O2-mediated internalization of photosensitizers from a ppa-bearing block copolymer. Angew. Chem., Int. Ed. 2020, 59, 3711–3717.

    Article  CAS  Google Scholar 

  11. Li, X. S.; Lee, D.; Huang, J. D.; Yoon, J. Phthalocyanine-assembled nanodots as photosensitizers for highly efficient type I photoreactions in photodynamic therapy. Angew. Chem., Int. Ed. 2018, 57, 9885–9890.

    Article  CAS  Google Scholar 

  12. Xu, X. L.; Deng, G. J.; Sun, Z. H.; Luo, Y.; Liu, J. K.; Yu, X. H.; Zhao, Y.; Gong, P.; Liu, G. Z.; Zhang, P. F. et al. A biomimetic aggregation-induced emission photosensitizer with antigen-presenting and hitchhiking function for lipid droplet targeted photodynamic immunotherapy. Adv. Mater. 2021, 33, 2102322.

    Article  CAS  Google Scholar 

  13. Lucky, S. S.; Soo, K. C.; Zhang, Y. Nanoparticles in photodynamic therapy. Chem. Rev. 2015, 115, 1990–2042.

    Article  CAS  Google Scholar 

  14. Wang, K. K.; Zhang, Y. F.; Wang, J.; Yuan, A. H.; Sun, M. J.; Wu, J. H.; Hu, Y. Q. Self-assembled IR780-loaded transferrin nanoparticles as an imaging, targeting and PDT/PTT agent for cancer therapy. Sci. Rep. 2016, 6, 27421.

    Article  Google Scholar 

  15. Tang, Y. Y.; Xue, L.; Yu, Q.; Chen, D. P.; Cheng, Z. J.; Wang, W. J.; Shao, J. J.; Dong, X. C. Smart Aza-BODIPY photosensitizer for tumor microenvironment-enhanced cancer phototherapy. ACS Appl. Bio Mater. 2019, 2, 5888–5897.

    Article  CAS  Google Scholar 

  16. Wang, J. P.; Zhang, B. L.; Sun, J. Y.; Wang, Y. H.; Wang, H. J. Nanomedicine-enabled modulation of tumor hypoxic microenvironment for enhanced cancer therapy. Adv. Ther. 2020, 3, 1900083.

    Article  Google Scholar 

  17. Zhang, Z.; Yang, J. R.; Min, Q. Q.; Ling, C. J.; Maiti, D.; Xu, J. Y.; Qin, L. Q.; Yang, K. Holo-lactoferrin modified liposome for relieving tumor hypoxia and enhancing radiochemotherapy of cancer. Small 2019, 15, 1803703.

    Article  Google Scholar 

  18. Chen, X. B.; Jin, R. R.; Jiang, Q.; Bi, Q. J.; He, T.; Song, X.; Barz, M.; Ai, H.; Shuai, X. T.; Nie, Y. Delivery of siHIF-1α to reconstruct tumor normoxic microenvironment for effective chemotherapeutic and photodynamic anticancer treatments. Small 2021, 17, 2100609.

    Article  CAS  Google Scholar 

  19. Chen, Y. X.; Xiang, H. J.; Zhuang, S. W.; Shen, Y. J.; Chen, Y.; Zhang, J. Oxygen-independent photocleavage of radical nanogenerator for near-IR-gated and H2O-mediated free-radical nanotherapy. Adv. Mater. 2021, 33, 2100129.

    Article  CAS  Google Scholar 

  20. Fan, W. P.; Bu, W. B.; Shen, B.; He, Q. J.; Cui, Z. W.; Liu, Y. Y.; Zheng, X. P.; Zhao, K. L.; Shi, J. L. Intelligent MnO2 nanosheets anchored with upconversion nanoprobes for concurrent pH-/H2O2-responsive UCL imaging and oxygen-elevated synergetic therapy. Adv. Mater. 2015, 27, 4155–4161.

    Article  CAS  Google Scholar 

  21. Lu, Y.; Song, G.; He, B.; Zhang, H.; Wang, X. Q.; Zhou, D. M.; Dai, W. B.; Zhang, Q. Strengthened tumor photodynamic therapy based on a visible nanoscale covalent organic polymer engineered by microwave assisted synthesis. Adv. Funct. Mater. 2020, 30, 2004834.

    Article  CAS  Google Scholar 

  22. Cheng, Y. H.; Cheng, H.; Jiang, C. X.; Qiu, X. F.; Wang, K. K.; Huan, W.; Yuan, A. H.; Wu, J. H.; Hu, Y. Q. Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy. Nat. Commun. 2015, 6, 8785.

    Article  CAS  Google Scholar 

  23. Liu, C. H.; Cao, Y.; Cheng, Y. R.; Wang, D. D.; Xu, T. L.; Su, L.; Zhang, X. J.; Dong, H. F. An open source and reduce expenditure ROS generation strategy for chemodynamic/photodynamic synergistic therapy. Nat. Commun. 2020, 11, 1735.

    Article  CAS  Google Scholar 

  24. Ouyang, J.; Wang, L. Q.; Chen, W. S.; Zeng, K.; Han, Y. J.; Xu, Y.; Xu, Q. F.; Deng, L.; Liu, Y. N. Biomimetic nanothylakoids for efficient imaging-guided photodynamic therapy for cancer. Chem. Commun. 2018, 54, 3468–3471.

    Article  CAS  Google Scholar 

  25. Barber, J. A mechanism for water splitting and oxygen production in photosynthesis. Nat. Plants 2017, 3, 17041.

    Article  CAS  Google Scholar 

  26. Li, Z.; Wang, W. Y.; Ding, C. M.; Wang, Z. L.; Liao, S. C.; Li, C. Biomimetic electron transport via multiredox shuttles from photosystem II to a photoelectrochemical cell for solar water splitting. Energy Environ. Sci. 2017, 10, 765–771.

    Article  CAS  Google Scholar 

  27. Zheng, D. W.; Li, B.; Xu, L.; Zhang, Q. L.; Fan, J. X.; Li, C. X.; Zhang, X. Z. Normalizing tumor microenvironment based on photosynthetic abiotic/biotic nanoparticles. ACS Nano 2018, 12, 6218–6227.

    Article  CAS  Google Scholar 

  28. Shen, S. K.; Wang, Y. Y.; Dong, J. X.; Zhang, R.; Parikh, A.; Chen, J. G.; Hu, D. D. Mimicking thylakoid membrane with chlorophyll/TiO2/lipid Co-assembly for light-harvesting and oxygen releasing. ACS Appl. Mater. Interfaces 2021, 13, 11461–11469.

    Article  CAS  Google Scholar 

  29. Cheng, Y.; Zheng, R. X.; Wu, X. Q.; Xu, K. Q.; Song, P. P.; Wang, Y. J.; Yan, J.; Chen, R.; Li, X. et al. Thylakoid membranes with unique photosystems used to simultaneously produce self-supplying oxygen and singlet oxygen for hypoxic tumor therapy. Adv. Healthc. Mater. 2021, 10, 2001666.

    Article  CAS  Google Scholar 

  30. Zhang, M.; Wang, W. T.; Wu, F.; Zheng, T.; Ashley, J.; Mohammadniaei, M.; Zhang, Q. C.; Wang, M. Q.; Li, L.; Shen, J. et al. Biodegradable Poly(γ-glutamic acid)@glucose oxidase@carbon dot nanoparticles for simultaneous multimodal imaging and synergetic cancer therapy. Biomaterials 2020, 252, 120106.

    Article  CAS  Google Scholar 

  31. Wu, M.; Wu, L. J.; Li, J.; Zhang, D.; Lan, S. Y.; Zhang, X. L.; Lin, X. Y.; Liu, G.; Liu, X. L.; Liu, J. F. Self-luminescing theranostic nanoreactors with intraparticle relayed energy transfer for tumor microenvironment activated imaging and photodynamic therapy. Theranostics 2019, 9, 20–33.

    Article  CAS  Google Scholar 

  32. Théry, C.; Witwer, K. W.; Aikawa, E.; Alcaraz, M. J.; Anderson, J. D.; Andriantsitohaina, R.; Antoniou, A.; Arab, T.; Archer, F.; Atkin-Smith, G. K. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018, 7, 1535750.

    Article  Google Scholar 

  33. Loudya, N.; Mishra, P.; Takahagi, K.; Uehara-Yamaguchi, Y.; Inoue, K.; Bogre, L.; Mochida, K.; López-Juez, E. Cellular and transcriptomic analyses reveal two-staged chloroplast biogenesis underpinning photosynthesis build-up in the wheat leaf. Genome Biol. 2021, 22, 151.

    Article  Google Scholar 

  34. Lu, Y. D.; Gan, Q. H.; Iwai, M.; Alboresi, A.; Burlacot, A.; Dautermann, O.; Takahashi, H.; Crisanto, T.; Peltier, G.; Morosinotto, T. et al. Role of an ancient light-harvesting protein of PSI in light absorption and photoprotection. Nat. Commun. 2021, 12, 679.

    Article  CAS  Google Scholar 

  35. Liu, H. L.; Huang, L. L.; Mao, M. C.; Ding, J. J.; Wu, G. H.; Fan, W. L.; Yang, T. R.; Zhang, M. J.; Huang, Y. Y.; Xie, H. Y. Viral protein-pseudotyped and siRNA-electroporated extracellular vesicles for cancer immunotherapy. Adv. Funct. Mater. 2020, 30, 2006515.

    Article  CAS  Google Scholar 

  36. Ding, J. J.; Lu, G. H.; Nie, W. D.; Huang, L. L.; Zhang, Y. H.; Fan, W. L.; Wu, G. H.; Liu, H. L.; Xie, H. Y. Self-activatable photo-extracellular vesicle for synergistic trimodal anticancer therapy. Adv. Mater. 2021, 33, 2005562.

    Article  CAS  Google Scholar 

  37. Carvalho, A. M. S.; Heimfarth, L.; Pereira, E. W. M.; Oliveira, F. S.; Menezes, I. R. A.; Coutinho, H. D. M.; Picot, L.; Antoniolli, A. R.; Quintans, J. S. S.; Quintans-Júnior, L. J. Phytol, a chlorophyll component, produces antihyperalgesic, anti-inflammatory, and antiarthritic effects: Possible NFκB pathway involvement and reduced levels of the proinflammatory cytokines TNF-α and IL-6. J. Nat. Prod. 2020, 83, 1107–1117.

    Article  CAS  Google Scholar 

  38. Kuramoto, M.; Kawashima, N.; Tazawa, K.; Nara, K.; Fujii, M.; Noda, S.; Hashimoto, K.; Nozaki, K.; Okiji, T. Mineral trioxide aggregate suppresses pro-inflammatory cytokine expression via the calcineurin/nuclear factor of activated T cells/early growth response 2 pathway in lipopolysaccharide-stimulated macrophages. Int. Endod. J. 2020, 53, 1653–1665.

    Article  CAS  Google Scholar 

  39. Nie, W. D.; Wu, G. H.; Zhang, J. F.; Huang, L. L.; Ding, J. J.; Jiang, A. Q.; Zhang, Y. H.; Liu, Y. H.; Li, J. C.; Pu, K. Y. et al. Responsive exosome nano-bioconjugates for synergistic cancer therapy. Angew. Chem., Int. Ed. 2020, 59, 2018–2022.

    Article  CAS  Google Scholar 

  40. Xu, X. X.; Gong, X.; Wang, Y. Q.; Li, J.; Wang, H.; Wang, J. Y.; Sha, X. Y.; Li, Y. P.; Zhang, Z. W. Reprogramming tumor associated macrophages toward M1 phenotypes with nanomedicine for anticancer immunotherapy. Adv. Ther. 2020, 3, 1900181.

    Article  Google Scholar 

  41. Aminin, D.; Wang, Y. M. Macrophages as a “weapon” in anticancer cellular immunotherapy. Kaohsiung J. Med. Sci. 2021, 37, 749–758.

    Article  CAS  Google Scholar 

  42. Wang, H. R.; Guo, Y. F.; Wang, C.; Jiang, X.; Liu, H. H.; Yuan, A. H.; Yan, J.; Hu, Y. Q.; Wu, J. H. Light-controlled oxygen production and collection for sustainable photodynamic therapy in tumor hypoxia. Biomaterials 2021, 269, 120621.

    Article  CAS  Google Scholar 

  43. Semeraro, P.; Chimienti, G.; Altamura, E.; Fini, P.; Rizzi, V.; Cosma, P. Chlorophyll a in cyclodextrin supramolecular complexes as a natural photosensitizer for photodynamic therapy (PDT) applications. Mater. Sci. Eng.: C 2018, 85, 47–56.

    Article  CAS  Google Scholar 

  44. Yao, C.; Wang, W. X.; Wang, P. Y.; Zhao, M. Y.; Li, X. M.; Zhang, F. Near-infrared upconversion mesoporous cerium oxide hollow biophotocatalyst for concurrent pH-/H2O2-responsive O2-evolving synergetic cancer therapy. Adv. Mater. 2018, 30, 1704833.

    Article  Google Scholar 

  45. Liu, J. A.; Liu, Y.; Bu, W. B.; Bu, J. W.; Sun, Y.; Du, J. L.; Shi, J. L. Ultrasensitive nanosensors based on upconversion nanoparticles for selective hypoxia imaging in vivo upon near-infrared excitation. J. Am. Chem. Soc. 2014, 136, 9701–9709.

    Article  CAS  Google Scholar 

  46. Zhao, M.; Leggett, E.; Bourke, S.; Poursanidou, S.; Carter-Searjeant, S.; Po, S.; Do Carmo, M. P.; Dailey, L. A.; Manning, P.; Ryan, S. G. et al. Theranostic near-infrared-active conjugated polymer nanoparticles. ACS Nano 2021, 15, 8790–8802.

    Article  CAS  Google Scholar 

  47. Chen, H. C.; Tian, J. W.; He, W. J.; Guo, Z. J. H2O2-activatable and O2-evolving nanoparticles for highly efficient and selective photodynamic therapy against hypoxic tumor cells. J. Am. Chem. Soc. 2015, 137, 1539–1547.

    Article  CAS  Google Scholar 

  48. Movahedi, K.; Laoui, D.; Gysemans, C.; Baeten, M.; Stangé, G.; Van Den Bossche, J.; Mack, M.; Pipeleers, D.; Veld, P. I.; De Baetselier, P. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010, 70, 5728–5739.

    Article  CAS  Google Scholar 

  49. Frank, A. C.; Ebersberger, S.; Fink, A. F.; Lampe, S.; Weigert, A.; Schmid, T.; Ebersberger, I.; Syed, S. N.; Brüne, B. Apoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype. Nat. Commun. 2019, 10, 1135.

    Article  Google Scholar 

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Acknowledgments

This work was funded by the National Natural Science Foundation of China (Nos. 21874011, 91859123, and 32101140), the National Science Fund for Distinguished Young Scholars (No. 22025401), the China Postdoctoral Science Foundation (No. 2020M680396). China Postdoctoral Science Foundation (Nos. 2021TQ0037 and 2021M690405). The National Natural Science Foundation of China (No. 21904012). The authors thank Biological & Medical Engineering Core Facilities (Beijing Institute of Technology) for providing advanced equipment.

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Correspondence to Ruili Yang or Hai-Yan Xie.

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Liu, H., Lei, Y., Nie, W. et al. Immunomodulatory hybrid bio-nanovesicle for self-promoted photodynamic therapy. Nano Res. 15, 4233–4242 (2022). https://doi.org/10.1007/s12274-021-4050-3

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