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Medicinal plant-derived mtDNA via nanovesicles induces the cGAS-STING pathway to remold tumor-associated macrophages for tumor regression

Liu, Jinfeng, Xiang, Jiaxin, Jin, Cuiyuan, Ye, Lusha, Wang, Lei, Gao, Yanan, Lv, Nianyin, Zhang, Junfeng, You, Fuping, Qiao, Hongzhi, Shi, Liyun·2023·Journal of Nanobiotechnology
DOI 10.1186/s12951-023-01835-0PMC PMC9990354

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Abstract

Plant-derived nanovesicles (PDNVs) have been proposed as a major mechanism for the inter-kingdom interaction and communication, but the effector components enclosed in the vesicles and the mechanisms involved are largely unknown. The plant Artemisia annua is known as an anti-malaria agent that also exhibits a wide range of biological activities including the immunoregulatory and anti-tumor properties with the mechanisms to be further addressed. Here, we isolated and purified the exosome-like particles from A. annua , which were characterized by nano-scaled and membrane-bound shape and hence termed artemisia-derived nanovesicles (ADNVs). Remarkably, the vesicles demonstrated to inhibit tumor growth and boost anti-tumor immunity in a mouse model of lung cancer, primarily through remolding the tumor microenvironment and reprogramming tumor-associated macrophages (TAMs). We identified plant-derived mitochondrial DNA (mtDNA), upon internalized into TAMs via the vesicles, as a major effector molecule to induce the cGAS-STING pathway driving the shift of pro-tumor macrophages to anti-tumor phenotype. Furthermore, our data showed that administration of ADNVs greatly improved the efficacy of PD-L1 inhibitor, a prototypic immune checkpoint inhibitor, in tumor-bearing mice. Together, the present study, for the first time, to our knowledge, unravels an inter-kingdom interaction wherein the medical plant-derived mtDNA, via the nanovesicles, induces the immunostimulatory signaling in mammalian immune cells for resetting anti-tumor immunity and promoting tumor eradication. Graphical Abstract

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  1. Cong M, Tan S, Li S, Gao L, Huang L, Zhang HG, Qiao H. Technology insight: Plant-derived vesicles-How far from the clinical biotherapeutics and therapeutic drug carriers? Adv Drug Deliv Rev. 2022;182:114108. · DOI
  2. Pinedo M, de la Canal L, de Marcos LC. A call for Rigor and standardization in plant extracellular vesicle research. J Extracell Vesicles. 2021;10:e12048. · DOI
  3. Dad HA, Gu TW, Zhu AQ, Huang LQ, Peng LH. Plant exosome-like nanovesicles: emerging therapeutics and drug delivery nanoplatforms. Mol Ther. 2021;29:13–31. · DOI
  4. Kameli N, Dragojlovic-Kerkache A, Savelkoul P, Stassen FR. Plant-derived extracellular vesicles: current findings, challenges, and future applications. Membranes (Basel). 2021;11:1.
  5. Teng Y, Ren Y, Sayed M, Hu X, Lei C, Kumar A, Hutchins E, Mu J, Deng Z, Luo C, et al. Plant-derived exosomal MicroRNAs shape the gut microbiota. Cell Host Microbe. 2018;24:637-652 e638. · DOI · Paper page
  6. Sundaram K, Mu J, Kumar A, Behera J, Lei C, Sriwastva MK, Xu F, Dryden GW, Zhang L, Chen S, et al. Garlic exosome-like nanoparticles reverse high-fat diet induced obesity via the gut/brain axis. Theranostics. 2022;12:1220–46. · DOI
  7. Teng Y, Xu F, Zhang X, Mu J, Sayed M, Hu X, Lei C, Sriwastva M, Kumar A, Sundaram K, et al. Plant-derived exosomal microRNAs inhibit lung inflammation induced by exosomes SARS-CoV-2 Nsp12. Mol Ther. 2021;29:2424–40. · DOI
  8. Chen Q, Li Q, Liang Y, Zu M, Chen N, Canup BSB, Luo L, Wang C, Zeng L, Xiao B. Natural exosome-like nanovesicles from edible tea flowers suppress metastatic breast cancer via ROS generation and microbiota modulation. Acta Pharm Sin B. 2022;12:907–23. · DOI
  9. Lee R, Ko HJ, Kim K, Sohn Y, Min SY, Kim JA, Na D, Yeon JH. Anti-melanogenic effects of extracellular vesicles derived from plant leaves and stems in mouse melanoma cells and human healthy skin. J Extracell Vesicles. 2020;9:1703480. · DOI
  10. Han X, Wei Q, Lv Y, Weng L, Huang H, Wei Q, Li M, Mao Y, Hua D, Cai X, et al. Ginseng-derived nanoparticles potentiate immune checkpoint antibody efficacy by reprogramming the cold tumor microenvironment. Mol Ther. 2022;30:327–40. · DOI
  11. Tu Y. Artemisinin-A gift from traditional Chinese medicine to the world (Nobel lecture). Angew Chem Int Ed Engl. 2016;55:10210–26. · DOI
  12. Dolivo D, Weathers P, Dominko T. Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics. Acta Pharm Sin B. 2021;11:322–39. · DOI · Paper page
  13. Krishna S, Augustin Y, Wang J, Xu C, Staines HM, Platteeuw H, Kamarulzaman A, Sall A, Kremsner P. Repurposing antimalarials to tackle the COVID-19 pandemic. Trends Parasitol. 2021;37:8–11. · DOI
  14. An J, Minie M, Sasaki T, Woodward JJ, Elkon KB. Antimalarial drugs as immune modulators: new mechanisms for old drugs. Annu Rev Med. 2017;68:317–30. · DOI
  15. Li Q, Yuan Q, Jiang N, Zhang Y, Su Z, Lv L, Sang X, Chen R, Feng Y, Chen Q. Dihydroartemisinin regulates immune cell heterogeneity by triggering a cascade reaction of CDK and MAPK phosphorylation. Signal Transduct Target Ther. 2022;7:222. · DOI
  16. Augustin Y, Staines HM, Krishna S. Artemisinins as a novel anti-cancer therapy: Targeting a global cancer pandemic through drug repurposing. Pharmacol Ther. 2020;216:107706. · DOI
  17. Mekers VE, Kho VM, Ansems M, Adema GJ. cGAS/cGAMP/STING signal propagation in the tumor microenvironment: key role for myeloid cells in antitumor immunity. Radiother Oncol. 2022;1:1.
  18. Ritchie C, Carozza JA, Li L. Biochemistry, cell biology, and pathophysiology of the innate immune cGAS-cGAMP-STING pathway. Annu Rev Biochem. 2022;91:599–628. · DOI
  19. Xia L, Zhang C, Lv N, Liang Z, Ma T, Cheng H, Xia Y, Shi L. AdMSC-derived exosomes alleviate acute lung injury via transferring mitochondrial component to improve homeostasis of alveolar macrophages. Theranostics. 2022;12:2928–47. · DOI
  20. Lv N, Zhao Y, Liu X, Ye L, Liang Z, Kang Y, Dong Y, Wang W, Kolliputi N, Shi L. Dysfunctional telomeres through mitostress-induced cGAS/STING activation to aggravate immune senescence and viral pneumonia. Aging Cell. 2022;21:e13594. · DOI
  21. Todkar K, Chikhi L, Desjardins V, El-Mortada F, Pepin G, Germain M. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs. Nat Commun. 1971;2021:12.
  22. Bridgeman A, Maelfait J, Davenne T, Partridge T, Peng Y, Mayer A, Dong T, Kaever V, Borrow P, Rehwinkel J. Viruses transfer the antiviral second messenger cGAMP between cells. Science. 2015;349:1228–32. · DOI
  23. Erttmann SF, Swacha P, Aung KM, Brindefalk B, Jiang H, Hartlova A, Uhlin BE, Wai SN, Gekara NO. The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis. Immunity. 2022;55:847-861 e810. · DOI
  24. Gurdon C, Svab Z, Feng Y, Kumar D, Maliga P. Cell-to-cell movement of mitochondria in plants. Proc Natl Acad Sci USA. 2016;113:3395–400. · DOI
  25. Koulintchenko M, Konstantinov Y, Dietrich A. Plant mitochondria actively import DNA via the permeability transition pore complex. EMBO J. 2003;22:1245–54. · DOI
  26. Hertle AP, Haberl B, Bock R. Horizontal genome transfer by cell-to-cell travel of whole organelles. Sci Adv. 2021;7:1. · DOI
  27. Mantovani A, Allavena P, Marchesi F, Garlanda C. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov. 2022;1:1.
  28. Downey CM, Aghaei M, Schwendener RA, Jirik FR. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2’3’-cGAMP, induces M2 macrophage repolarization. PLoS ONE. 2014;9:e99988. · DOI
  29. Wang Q, Bergholz JS, Ding L, Lin Z, Kabraji SK, Hughes ME, He X, Xie S, Jiang T, Wang W, et al. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nat Commun. 2022;13:3022. · DOI
  30. Shen R, Liu D, Wang X, Guo Z, Sun H, Song Y, Wang D. DNA damage and activation of cGAS/STING pathway induce tumor microenvironment remodeling. Front Cell Dev Biol. 2021;9:828657. · DOI
  31. Luo K, Li N, Ye W, Gao H, Luo X, Cheng B. Activation of stimulation of interferon genes (STING) signal and cancer immunotherapy. Molecules. 2022;27:1. · DOI
  32. Benmerzoug S, Rose S, Bounab B, Gosset D, Duneau L, Chenuet P, Mollet L, Le Bert M, Lambers C, Geleff S, et al. STING-dependent sensing of self-DNA drives silica-induced lung inflammation. Nat Commun. 2018;9:5226. · DOI
  33. Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RRJ, Moecking J, De Nardo D, et al. TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS. Cell. 2020;183:636-649 e618. · DOI · Paper page
  34. Korman AJ, Garrett-Thomson SC, Lonberg N. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat Rev Drug Discov. 2022;21:509–28. · DOI
  35. Chen N, Sun J, Zhu Z, Cribbs AP, Xiao B. Edible plant-derived nanotherapeutics and nanocarriers: recent progress and future directions. Expert Opin Drug Deliv. 2022;19:409–19. · DOI
  36. Kim J, Li S, Zhang S, Wang J. Plant-derived exosome-like nanoparticles and their therapeutic activities. Asian J Pharm Sci. 2022;17:53–69. · DOI
  37. Lange H, Gagliardi D. Catalytic activities, molecular connections, and biological functions of plant RNA exosome complexes. Plant Cell. 2022;34:967–88. · DOI
  38. Zhou Q, Ma K, Hu H, Xing X, Huang X, Gao H. Extracellular vesicles: their functions in plant-pathogen interactions. Mol Plant Pathol. 2022;23:760–71. · DOI
  39. Cao M, Yan H, Han X, Weng L, Wei Q, Sun X, Lu W, Wei Q, Ye J, Cai X, et al. Ginseng-derived nanoparticles alter macrophage polarization to inhibit melanoma growth. J Immunother Cancer. 2019;7:326. · DOI
  40. Ju S, Mu J, Dokland T, Zhuang X, Wang Q, Jiang H, Xiang X, Deng ZB, Wang B, Zhang L, et al. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Mol Ther. 2013;21:1345–57. · DOI
  41. Mohammadi S, Jafari B, Asgharian P, Martorell M, Sharifi-Rad J. Medicinal plants used in the treatment of Malaria: A key emphasis to Artemisia, Cinchona, Cryptolepis, and Tabebuia genera. Phytother Res. 2020;34:1556–69. · DOI
  42. Hu Y, Guo N, Yang T, Yan J, Wang W, Li X. The potential mechanisms by which artemisinin and its derivatives induce ferroptosis in the treatment of cancer. Oxid Med Cell Longev. 2022;2022:1458143. · DOI
  43. Cheong DHJ, Tan DWS, Wong FWS, Tran T. Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases. Pharmacol Res. 2020;158:104901. · DOI
  44. Wu H, Hu B, Zhou X, Zhou C, Meng J, Yang Y, Zhao X, Shi Z, Yan S. Artemether attenuates LPS-induced inflammatory bone loss by inhibiting osteoclastogenesis and bone resorption via suppression of MAPK signaling pathway. Cell Death Dis. 2018;9:498. · DOI
  45. Ghanbari M, Sadeghimahalli F. Aqueous and alcoholic extracts of Artemisia annua L. improved insulin resistance via decreasing TNF-alpha, IL-6 and free fatty acids in high-fat diet/streptozotocin-induced diabetic mice. Avicenna J Phytomed. 2022;12:54–66.
  46. Kayani SI, Shen Q, Rahman SU, Fu X, Li Y, Wang C, Hassani D, Tang K. Transcriptional regulation of flavonoid biosynthesis in Artemisia annua by AaYABBY5. Hortic Res. 2021;8:257. · DOI
  47. Apaza Ticona L, Bermejo P, Guerra JA, Abad MJ, Beltran M, Martin Lazaro R, Alcami J, Bedoya LM. Ethanolic extract of Artemisia campestris subsp. glutinosa (Besser) Batt. inhibits HIV-1 replication in vitro through the activity of terpenes and flavonoids on viral entry and NF-kappaB pathway. J Ethnopharmacol. 2020;263:113163. · DOI
  48. Xu XH, Yuan TJ, Dad HA, Shi MY, Huang YY, Jiang ZH, Peng LH. Plant exosomes as novel nanoplatforms for MicroRNA transfer stimulate neural differentiation of stem cells in vitro and in vivo. Nano Lett. 2021;21:8151–9. · DOI
  49. Zacheo A, Bizzarro L, Blasi L, Piccirillo C, Cardone A, Gigli G, Ragusa A, Quarta A. Lipid-based nanovesicles for simultaneous intracellular delivery of hydrophobic, hydrophilic, and amphiphilic species. Front Bioeng Biotechnol. 2020;8:690. · DOI
  50. Nakamura T, Sato T, Endo R, Sasaki S, Takahashi N, Sato Y, Hyodo M, Hayakawa Y, Harashima H. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation. J Immunother Cancer. 2021;9:1. · DOI
  51. Deng Z, Rong Y, Teng Y, Mu J, Zhuang X, Tseng M, Samykutty A, Zhang L, Yan J, Miller D, et al. Broccoli-derived nanoparticle inhibits mouse colitis by activating dendritic cell AMP-activated protein kinase. Mol Ther. 2017;25:1641–54. · DOI
  52. Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018;17:887–904. · DOI
  53. Wang B, Zhuang X, Deng ZB, Jiang H, Mu J, Wang Q, Xiang X, Guo H, Zhang L, Dryden G, et al. Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit. Mol Ther. 2014;22:522–34. · DOI
  54. Skopelja-Gardner S, An J, Elkon KB. Role of the cGAS-STING pathway in systemic and organ-specific diseases. Nat Rev Nephrol. 2022;18:558–72. · DOI
  55. Miao L, Qi J, Zhao Q, Wu QN, Wei DL, Wei XL, Liu J, Chen J, Zeng ZL, Ju HQ, et al. Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells. Theranostics. 2020;10:498–515. · DOI
  56. Zhong W, Rao Z, Xu J, Sun Y, Hu H, Wang P, Xia Y, Pan X, Tang W, Chen Z, et al. Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation. Aging Cell. 2022;21:e13622. · DOI
  57. Maingi V, Rothemund PWK. Properties of DNA- and protein-scaffolded lipid nanodiscs. ACS Nano. 2021;15:751–64. · DOI
  58. Li Y, Ye Z, Yang H, Xu Q. Tailoring combinatorial lipid nanoparticles for intracellular delivery of nucleic acids, proteins, and drugs. Acta Pharm Sin B. 2022;12:2624–39. · DOI
  59. Hayman TJ, Baro M, MacNeil T, Phoomak C, Aung TN, Cui W, Leach K, Iyer R, Challa S, Sandoval-Schaefer T, et al. STING enhances cell death through regulation of reactive oxygen species and DNA damage. Nat Commun. 2021;12:2327. · DOI
  60. Wang-Bishop L, Wehbe M, Shae D, James J, Hacker BC, Garland K, Chistov PP, Rafat M, Balko JM, Wilson JT. Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma. J Immunother Cancer. 2020;8:1. · DOI
  61. Chattopadhyay S, Liu YH, Fang ZS, Lin CL, Lin JC, Yao BY, Hu CJ. Synthetic immunogenic cell death mediated by intracellular delivery of STING agonist nanoshells enhances anticancer chemo-immunotherapy. Nano Lett. 2020;20:2246–56. · DOI
  62. Zhou Y, Guo Y, Chen L, Zhang X, Wu W, Yang Z, Li X, Wang Y, Hu Z, Wang Z. Co-delivery of phagocytosis checkpoint and STING agonist by a Trojan horse nanocapsule for orthotopic glioma immunotherapy. Theranostics. 2022;12:5488–503. · DOI

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Metadata

Authors
Liu, J., Xiang, J., Jin, C., Ye, L., Wang, L., Gao, Y., Lv, N., Zhang, J., You, F., Qiao, H., & Shi, L.
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2023-03-06
Volume
21
Issue
1
ISSN
1477-3155
DOI
10.1186/s12951-023-01835-0
PMC
PMC9990354
Cited by
132
References
2
Language
en
Licence
Funders
  • National Natural Science Foundation of China (82200677, 81991523)
  • National Key Research and Development Program of China (2018YFC1705900)

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