Engineered plant extracellular vesicles for autoimmune diseases therapy

Davidson, A.; Diamond, B. Autoimmune diseases. N. Engl. J. Med. 2001, 345, 340–350.

Zhang, Y. N.; Li, Y. N.; Zhang, J. L.; Chen, X. H.; Zhang, R. F.; Sun, G. M.; Jiang, B.; Fan, K. L.; Li, Z. G.; Yan, X. Y. Nanocage-based capture-detection system for the clinical diagnosis of autoimmune disease. Small 2021, 17, e2101655.

Banchereau, R.; Cepika, A. M.; Pascual, V. Systems approaches to human autoimmune diseases. Curr. Opin. Immunol. 2013, 25, 598–605.

Wang, L. F.; Wang, F. S.; Gershwin, M. E. Human autoimmune diseases: A comprehensive update. J. Intern. Med. 2015, 278, 369–395.

Konforte, D.; Diamandis, E. P.; van Venrooij, W. J.; Lories, R.; Ward, M. M. Autoimmune diseases: Early diagnosis and new treatment strategies. Clin. Chem. 2012, 58, 1510–1514.

Danne, C.; Michaudel, C.; Skerniskyte, J.; Planchais, J.; Magniez, A.; Agus, A.; Michel, M. L.; Lamas, B.; Costa, G. D.; Spatz, M. et al. CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival. Gut. 2023, 72, 1081–1092.

Jiang, Y. Y.; Li, J. D.; Xue, X.; Yin, Z. F.; Xu, K.; Su, J. C. Engineered extracellular vesicles for bone therapy. Nano Today 2022, 44, 101487.

Sun, J. R.; Yin, Z. F.; Wang, X. H.; Su, J. C. Exosome-laden hydrogels: A novel cell-free strategy for in-situ bone tissue regeneration. Front. Bioeng. Biotechnol. 2022, 10, 866208.

Maas, S. L. N.; Breakefield, X. O.; Weaver, A. M. Extracellular vesicles: Unique intercellular delivery vehicles. Trends Cell Biol. 2017, 27, 172–188.

Mathieu, M.; Martin-Jaular, L.; Lavieu, G.; Théry, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 2019, 21, 9–17.

Liu, H.; Sun, J. R.; Wang, M. K.; Wang, S. C.; Su, J. C.; Xu, C. Intestinal organoids and organoids extracellular vesicles for inflammatory bowel disease treatment. Chem. Eng. J. 2023, 465, 142842.

Liu, H.; Zhang, H.; Han, Y. F.; Hu, Y.; Geng, Z.; Su, J. C. Bacterial extracellular vesicles-based therapeutic strategies for bone and soft tissue tumors therapy. Theranostics 2022, 12, 6576–6594.

Ludwig, N.; Yerneni, S. S.; Azambuja, J. H.; Gillespie, D. G.; Menshikova, E. V.; Jackson, E. K.; Whiteside, T. L. Tumor-derived exosomes promote angiogenesis via adenosine A_2B receptor signaling. Angiogenesis 2020, 23, 599–610.

Xu, F.; Fei, Z. Y.; Dai, H. X.; Xu, J. L.; Fan, Q.; Shen, S. F.; Zhang, Y.; Ma, Q. L.; Chu, J. C.; Peng, F. et al. Mesenchymal stem cell-derived extracellular vesicles with high PD-L1 expression for autoimmune diseases treatment. Adv. Mater. 2022, 34, e2106265.

Sosnowska, A.; Czystowska-Kuzmicz, M.; Golab, J. Extracellular vesicles released by ovarian carcinoma contain arginase 1 that mitigates antitumor immune response. OncoImmunology 2019, 8, e1655370.

Halperin, W.; Jensen, W. A. Ultrastructural changes during growth and embryogenesis in carrot cell cultures. J. Ultrastruct. Res. 1967, 18, 428–443.

Sarvarian, P.; Samadi, P.; Gholipour, E.; Shams Asenjan, K.; Hojjat-Farsangi, M.; Motavalli, R.; Motavalli Khiavi, F.; Yousefi, M. Application of emerging plant-derived nanoparticles as a novel approach for nano-drug delivery systems. Immunol. Invest. 2022, 51, 1039–1059.

Yang, C. H.; Zhang, M. Z.; Merlin, D. Advances in plant-derived edible nanoparticle-based lipid nano-drug delivery systems as therapeutic nanomedicines. J. Mater. Chem. B 2018, 6, 1312–1321.

Baldini, N.; Torreggiani, E.; Roncuzzi, L.; Perut, F.; Zini, N.; Avnet, S. Exosome-like nanovesicles isolated from citrus limon L exert antioxidative effect. Curr. Pharm. Biotechnol. 2018, 19, 877–885.

Song, H. Y.; Li, X. Q.; Zhao, Z. C.; Qian, J.; Wang, Y.; Cui, J.; Weng, W. Z.; Cao, L. H.; Chen, X.; Hu, Y. et al. Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes. Nano Lett. 2019, 19, 3040–3048.

Maeda, Y.; Farina, N. H.; Matzelle, M. M.; Fanning, P. J.; Lian, J. B.; Gravallese, E. M. Synovium-derived MicroRNAs regulate bone pathways in rheumatoid arthritis. J. Bone Miner. Res. 2017, 32, 461–472.

Dad, H. A.; Gu, T. W.; Zhu, A. Q.; Huang, L. Q.; Peng, L. H. Plant exosome-like nanovesicles: Emerging therapeutics and drug delivery nanoplatforms. Mol. Ther. 2021, 29, 13–31.

Cui, Y.; Gao, J. Y.; He, Y. L.; Jiang, L. W. Plant extracellular vesicles. Protoplasma 2020, 257, 3–12.

An, Q. L.; van Bel, A. J. E.; Hückelhoven, R. Do plant cells secrete exosomes derived from multivesicular bodies. Plant Signal. Behav. 2007, 2, 4–7.

Movahed, N.; Cabanillas, D. G.; Wan, J.; Vali, H.; Laliberté, J. F.; Zheng, H. Q. Turnip mosaic virus components are released into the extracellular space by vesicles in infected leaves. Plant Physiol. 2019, 180, 1375–1388.

Wang, J.; Ding, Y.; Wang, J. Q.; Hillmer, S.; Miao, Y. S.; Lo, S. W.; Wang, X. F.; Robinson, D. G.; Jiang, L. W. EXPO, an exocyst-positive organelle distinct from multivesicular endosomes and autophagosomes, mediates cytosol to cell wall exocytosis in Arabidopsis and tobacco cells. Plant Cell 2010, 22, 4009–4030.

Hatsugai, N.; Iwasaki, S.; Tamura, K.; Kondo, M.; Fuji, K.; Ogasawara, K.; Nishimura, M.; Hara-Nishimura, I. A novel membrane fusion-mediated plant immunity against bacterial pathogens. Genes Dev. 2009, 23, 2496–2506.

Wang, B. M.; Zhuang, X. Y.; Deng, Z. B.; Jiang, H.; Mu, J. Y.; Wang, Q. L.; Xiang, X. Y.; Guo, H. X.; Zhang, L. F.; Dryden, G. et al. Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit. Mol. Ther. 2014, 22, 522–534.

Ju, S. W.; Mu, J. Y.; Dokland, T.; Zhuang, X. Y.; Wang, Q. L.; Jiang, H.; Xiang, X. Y.; Deng, Z. B.; Wang, B. M.; Zhang, L. F. et al. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Mol. Ther. 2013, 21, 1345–1357.

Mayran, N.; Parton, R. G.; Gruenberg, J. Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of animal cells. EMBO J. 2003, 22, 3242–3253.

White, I. J.; Bailey, L. M.; Aghakhani, M. R.; Moss, S. E.; Futter, C. E. EGF stimulates annexin 1-dependent inward vesiculation in a multivesicular endosome subpopulation. EMBO J. 2006, 25, 1–12.

Pocsfalvi, G.; Turiák, L.; Ambrosone, A.; Del Gaudio, P.; Puska, G.; Fiume, I.; Silvestre, T.; Vékey, K. Protein biocargo of citrus fruit-derived vesicles reveals heterogeneous transport and extracellular vesicle populations. J. Plant Physiol. 2018, 229, 111–121.

Raimondo, S.; Naselli, F.; Fontana, S.; Monteleone, F.; Lo Dico, A.; Saieva, L.; Zito, G.; Flugy, A.; Manno, M.; Di Bella, M. A. et al. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death. Oncotarget 2015, 6, 19514–19527.

Li, D.; Yao, X. L.; Yue, J. X.; Fang, Y. P.; Cao, G. F.; Midgley, A. C.; Nishinari, K.; Yang, Y. L. Advances in bioactivity of MicroRNAs of plant-derived exosome-like nanoparticles and milk-derived extracellular vesicles. J. Agric. Food Chem. 2022, 70, 6285–6299.

Zhang, M. Z.; Viennois, E.; Prasad, M.; Zhang, Y. C.; Wang, L. X.; Zhang, Z.; Han, M. K.; Xiao, B.; Xu, C. L.; Srinivasan, S. et al. Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer. Biomaterials 2016, 101, 321–340.

Zhuang, X. Y.; Deng, Z. B.; Mu, J. Y.; Zhang, L. F.; Yan, J.; Miller, D.; Feng, W. K.; McClain, C. J.; Zhang, H. G. Ginger-derived nanoparticles protect against alcohol-induced liver damage. J. Extracell. Vesicles 2015, 4, 28713.

Perut, F.; Roncuzzi, L.; Avnet, S.; Massa, A.; Zini, N.; Sabbadini, S.; Giampieri, F.; Mezzetti, B.; Baldini, N. Strawberry-derived exosome-like nanoparticles prevent oxidative stress in human mesenchymal stromal cells. Biomolecules 2021, 11, 87.

Woith, E.; Guerriero, G.; Hausman, J. F.; Renaut, J.; Leclercq, C. C.; Weise, C.; Legay, S.; Weng, A.; Melzig, M. F. Plant extracellular vesicles and nanovesicles: Focus on secondary metabolites, proteins and lipids with perspectives on their potential and sources. Int. J. Mol. Sci. 2021, 22, 3719.

De Robertis, M.; Sarra, A.; D'Oria, V.; Mura, F.; Bordi, F.; Postorino, P.; Fratantonio, D. Blueberry-derived exosome-like nanoparticles counter the response to TNF-α-induced change on gene expression in EA hy926 cells. Biomolecules 2020, 10, 742.

Li, Z. F.; Wang, H. Z.; Yin, H. R.; Bennett, C.; Zhang, H. G.; Guo, P. X. Arrowtail RNA for ligand display on ginger exosome-like nanovesicles to systemic deliver siRNA for cancer suppression. Sci. Rep. 2018, 8, 14644.

Cao, M.; Yan, H. J.; Han, X.; Weng, L.; Wei, Q.; Sun, X. Y.; Lu, W. G.; Wei, Q. Y.; Ye, J.; Cai, X. T. et al. Ginseng-derived nanoparticles alter macrophage polarization to inhibit melanoma growth. J. Immunother. Cancer 2019, 7, 326.

Wang, Q. L.; Zhuang, X. Y.; Mu, J. Y.; Deng, Z. B.; Jiang, H.; Zhang, L. F.; Xiang, X. Y.; Wang, B.; Yan, J.; Miller, D. et al. Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids. Nat. Commun. 2013, 4, 1867.

Khoobchandani, M.; Zambre, A.; Katti, K.; Lin, C. H.; Katti, K. V. Green nanotechnology from brassicaceae: Development of broccoli phytochemicals-encapsulated gold nanoparticles and their applications in nanomedicine. Int. J. Green Nanotechnol. 2013, 1, 1943089213509474.

Fujita, D.; Arai, T.; Komori, H.; Shirasaki, Y.; Wakayama, T.; Nakanishi, T.; Tamai, I. Apple-derived nanoparticles modulate expression of organic-anion-transporting polypeptide (OATP) 2B1 in caco-2 cells. Mol. Pharm. 2018, 15, 5772–5780.

Gonda, A.; Kabagwira, J.; Senthil, G. N.; Wall, N. R. Internalization of exosomes through receptor-mediated endocytosis. Mol. Cancer. Res. 2019, 17, 337–347.

Nanjundaiah, S. M.; Venkatesha, S. H.; Yu, H.; Tong, L.; Stains, J. P.; Moudgil, K. D. Celastrus and its bioactive celastrol protect against bone damage in autoimmune arthritis by modulating osteoimmune cross-talk. J. Biol. Chem. 2012, 287, 22216–22226.

Song, H. L.; Canup, B. S. B.; Ngo, V. L.; Denning, T. L.; Garg, P.; Laroui, H. Internalization of garlic-derived nanovesicles on liver cells is triggered by interaction with CD98. ACS Omega 2020, 5, 23118–23128.

Teng, Y.; Ren, Y.; Sayed, M.; Hu, X.; Lei, C.; Kumar, A.; Hutchins, E.; Mu, J. Y.; Deng, Z. B.; Luo, C. et al. Plant-derived exosomal MicroRNAs shape the gut microbiota. Cell Host Microbe 2018, 24, 637–652.e8.

Xu, X. H.; Yuan, T. J.; Dad, H. A.; Shi, M. Y.; Huang, Y. Y.; Jiang, Z. H.; Peng, L. H. Plant exosomes as novel nanoplatforms for MicroRNA transfer stimulate neural differentiation of stem cells in vitro and in vivo. Nano Lett. 2021, 21, 8151–8159.

Hannafon, B. N.; Gin, A. L.; Xu, Y. F.; Bruns, M.; Calloway, C. L.; Ding, W. Q. Metastasis-associated protein 1 (MTA1) is transferred by exosomes and contributes to the regulation of hypoxia and estrogen signaling in breast cancer cells. Cell Commun. Signal. 2019, 17, 13.

Boriachek, K.; Islam, M. N.; Möller, A.; Salomon, C.; Nguyen, N. T.; Hossain, M. S. A.; Yamauchi, Y.; Shiddiky, M. J. A. Biological functions and current advances in isolation and detection strategies for exosome nanovesicles. Small 2018, 14, 1702153.

Potestà, M.; Minutolo, A.; Gismondi, A.; Canuti, L.; Kenzo, M.; Roglia, V.; Macchi, F.; Grelli, S.; Canini, A.; Colizzi, V. et al. Cytotoxic and apoptotic effects of different extracts of moringa oleifera lam on lymphoid and monocytoid cells. Exp. Ther. Med. 2019, 18, 5–17.

Kalarikkal, S. P.; Prasad, D.; Kasiappan, R.; Chaudhari, S. R.; Sundaram, G. M. A cost-effective polyethylene glycol-based method for the isolation of functional edible nanoparticles from ginger rhizomes. Sci. Rep. 2020, 10, 4456.

You, J. Y.; Kang, S. J.; Rhee, W. J. Isolation of cabbage exosome-like nanovesicles and investigation of their biological activities in human cells. Bioact. Mater. 2021, 6, 4321–4332.

You, D. G.; Lim, G. T.; Kwon, S.; Um, W.; Oh, B. H.; Song, S. H.; Lee, J.; Jo, D. G.; Cho, Y. W.; Park, J. H. Metabolically engineered stem cell-derived exosomes to regulate macrophage heterogeneity in rheumatoid arthritis. Sci. Adv. 2021, 7, eabe0083.

Yang, M.; Liu, X. Y.; Luo, Q. Q.; Xu, L. L.; Chen, F. X. An efficient method to isolate lemon derived extracellular vesicles for gastric cancer therapy. J. Nanobiotechnology 2020, 18, 100.

Huang, Y. F.; Wang, S. M.; Cai, Q.; Jin, H. L. Effective methods for isolation and purification of extracellular vesicles from plants. J. Integr. Plant Biol. 2021, 63, 2020–2030.

Zhuang, X. Y.; Teng, Y.; Samykutty, A.; Mu, J. Y.; Deng, Z. B.; Zhang, L. F.; Cao, P. X.; Rong, Y.; Yan, J.; Miller, D. et al. Grapefruit-derived nanovectors delivering therapeutic miR17 through an intranasal route inhibit brain tumor progression. Mol. Ther. 2016, 24, 96–105.

Rider, M. A.; Hurwitz, S. N.; Meckes, D. G. Jr. ExtraPEG:A polyethylene glycol-based method for enrichment of extracellular vesicles. Sci. Rep. 2016, 6, 23978.

Deregibus, M. C.; Figliolini, F.; D'Antico, S.; Manzini, P. M.; Pasquino, C.; De Lena, M.; Tetta, C.; Brizzi, M. F.; Camussi, G. Charge-based precipitation of extracellular vesicles. Int. J. Mol. Med. 2016, 38, 1359–1366.

Nordin, J. Z.; Lee, Y.; Vader, P.; Mäger, I.; Johansson, H. J.; Heusermann, W.; Wiklander, O. P. B.; Hällbrink, M.; Seow, Y.; Bultema, J. J. et al. Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties. Nanomedicine 2015, 11, 879–883.

Li, P.; Kaslan, M.; Lee, S. H.; Yao, J.; Gao, Z. Q. Progress in exosome isolation techniques. Theranostics 2017, 7, 789–804.

Lei, C.; Mu, J. Y.; Teng, Y.; He, L. Q.; Xu, F. Y.; Zhang, X. C.; Sundaram, K.; Kumar, A.; Sriwastva, M. K.; Lawrenz, M. B. et al. Lemon exosome-like nanoparticles-manipulated probiotics protect mice from C. diff infection. iScience 2020, 23, 101571.

Liu, B. L.; Lu, Y. Z.; Chen, X. Y.; Muthuraj, P. G.; Li, X. Z.; Pattabiraman, M.; Zempleni, J.; Kachman, S. D.; Natarajan, S. K.; Yu, J. J. Protective role of shiitake mushroom-derived exosome-like nanoparticles in D-galactosamine and lipopolysaccharide-induced acute liver injury in mice. Nutrients 2020, 12, 477.

Lee, R.; Ko, H. J.; Kim, K.; Sohn, Y.; Min, S. Y.; Kim, J. A.; Na, D.; Yeon, J. H. 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.

Kumar, A.; Ren, Y.; Sundaram, K.; Mu, J. Y.; Sriwastva, M. K.; Dryden, G. W.; Lei, C.; Zhang, L. F.; Yan, J.; Zhang, X. et al. miR-375 prevents high-fat diet-induced insulin resistance and obesity by targeting the aryl hydrocarbon receptor and bacterial tryptophanase (tnaA) gene. Theranostics 2021, 11, 4061–4077.

Sundaram, K.; Miller, D. P.; Kumar, A.; Teng, Y.; Sayed, M.; Mu, J. Y.; Lei, C.; Sriwastva, M. K.; Zhang, L. F.; Yan, J. et al. Plant-derived exosomal nanoparticles inhibit pathogenicity of Porphyromonas gingivalis. iScience 2019, 21, 308–327.

Teng, Y.; Xu, F. Y.; Zhang, X. C.; Mu, J. Y.; 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, 2424–2440.

Zhang, H. Y.; Yang, M.; Wu, X.; Li, Q. X.; Li, X.; Zhao, Y. S.; Du, F. K.; Chen, Y.; Wu, Z. G.; Xiao, Z. G. et al. The distinct roles of exosomes in tumor-stroma crosstalk within gastric tumor microenvironment. Pharmacol. Res. 2021, 171, 105785.

Xu, Z. J.; Zeng, S. S.; Gong, Z. C.; Yan, Y. L. Exosome-based immunotherapy: A promising approach for cancer treatment. Mol. Cancer 2020, 19, 160.

Li, L.; Zhang, L. L.; Montgomery, K. C.; Jiang, L.; Lyon, C. J.; Hu, T. Y. Advanced technologies for molecular diagnosis of cancer: State of pre-clinical tumor-derived exosome liquid biopsies. Mater. Today. Bio 2023, 18, 100538.

Barreiro, K.; Lay, A. C.; Leparc, G.; Tran, V. D. T.; Rosler, M.; Dayalan, L.; Burdet, F.; Ibberson, M.; Coward, R. J. M.; Huber, T. B. et al. An in vitro approach to understand contribution of kidney cells to human urinary extracellular vesicles. J. Extracell. Vesicles 2023, 12, e12304.

Zhang, Y. M.; Cai, Z. C.; Shen, Y. L.; Lu, Q. Z.; Gao, W.; Zhong, X.; Yao, K.; Yuan, J.; Liu, H. B. Hydrogel-load exosomes derived from dendritic cells improve cardiac function via Treg cells and the polarization of macrophages following myocardial infarction. J. Nanobiotechnol. 2021, 19, 271.

Kim, J.; Li, S. Y.; Zhang, S. Y.; Wang, J. X. Plant-derived exosome-like nanoparticles and their therapeutic activities. Asian J. Pharm. Sci. 2022, 17, 53–69.

Pinedo, M.; de la Canal, L.; de Marcos Lousa, C. A call for rigor and standardization in plant extracellular vesicle research. J. Extracell. Vesicles 2021, 10, e12048.

Logozzi, M.; Di Raimo, R.; Mizzoni, D.; Fais, S. The potentiality of plant-derived nanovesicles in human health-a comparison with human exosomes and artificial nanoparticles. Int. J. Mol. Sci. 2022, 23, 4919.

Shao, H. L.; Im, H.; Castro, C. M.; Breakefield, X.; Weissleder, R.; Lee, H. New technologies for analysis of extracellular vesicles. Chem. Rev. 2018, 118, 1917–1950.

Johnson, J.; Wu, Y. W.; Blyth, C.; Lichtfuss, G.; Goubran, H.; Burnouf, T. Prospective therapeutic applications of platelet extracellular vesicles. Trends Biotechnol. 2021, 39, 598–612.

Wiklander, O. P. B.; Brennan, M. Á.; Lötvall, J.; Breakefield, X. O.; El Andaloussi, S. Advances in therapeutic applications of extracellular vesicles. Sci. Transl. Med. 2019, 11, eaav8521.

Rao, D. A.; Gurish, M. F.; Marshall, J. L.; Slowikowski, K.; Fonseka, C. Y.; Liu, Y. Y.; Donlin, L. T.; Henderson, L. A.; Wei, K.; Mizoguchi, F. et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 2017, 542, 110–114.

Ma, D.; Xu, K.; Zhang, G. L.; Liu, Y.; Gao, J. F.; Tian, M.; Wei, C.; Li, J.; Zhang, L. Y. Immunomodulatory effect of human umbilical cord mesenchymal stem cells on T lymphocytes in rheumatoid arthritis. Int. Immunopharmacol. 2019, 74, 105687.

Shu, Y.; Hu, Q. H.; Long, H.; Chang, C.; Lu, Q. J.; Xiao, R. Epigenetic variability of CD4+CD25+ tregs contributes to the pathogenesis of autoimmune diseases. Clin. Rev. Allergy Immunol. 2017, 52, 260–272.

Yang, J.; Chu, Y. W.; Yang, X.; Gao, D.; Zhu, L. B.; Yang, X. R.; Wan, L. L.; Li, M. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009, 60, 1472–1483.

Wang, Y. L.; Zhang, H.; Hu, Y.; Jing, Y. Y.; Geng, Z.; Su, J. C. Bone repair biomaterials: A perspective from immunomodulation. Adv. Funct. Mater. 2022, 32, 2208639.

Guo, L. N.; Zhong, S. H.; Liu, P.; Guo, M.; Ding, J. S.; Zhou, W. H. Radicals scavenging MOFs enabling targeting delivery of siRNA for rheumatoid arthritis therapy. Small 2022, 18, e2202604.

Wang, Y. L.; Lin, Q. S.; Zhang, H.; Wang, S. C.; Cui, J.; Hu, Y.; Liu, J. L.; Li, M. M.; Zhang, K.; Zhou, F. J. et al. M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator. Bioact. Matter 2023, 28, 273–283.

Hot, A.; Miossec, P. Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Ann. Rheum. Dis. 2011, 70, 727–732.

Adami, S.; Cavani, A.; Rossi, F.; Girolomoni, G. The role of interleukin-17A in psoriatic disease. BioDrugs 2014, 28, 487–497.

Quiñonez-Flores, C. M.; González-Chávez, S. A.; Del Río Nájera, D.; Pacheco-Tena, C. Oxidative stress relevance in the pathogenesis of the rheumatoid arthritis: A systematic review. Biomed Res. Int. 2016, 2016, 6097417.

Ren, X. X.; Liu, H.; Wu, X. M.; Weng, W. Z.; Wang, X. H.; Su, J. C. Reactive oxygen species (ROS)-responsive biomaterials for the treatment of bone-related diseases. Front. Bioeng. Biotechnol. 2022, 9, 820468.

Mu, J. Y.; Zhuang, X. Y.; Wang, Q. L.; Jiang, H.; Deng, Z. B.; Wang, B. M.; Zhang, L. F.; Kakar, S.; Jun, Y.; Miller, D. et al. Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol. Nutr. Food Res. 2014, 58, 1561–1573.

Aquilano, K.; Ceci, V.; Gismondi, A.; De Stefano, S.; Iacovelli, F.; Faraonio, R.; Di Marco, G.; Poerio, N.; Minutolo, A.; Minopoli, G. et al. Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts. Commun. Biol. 2019, 2, 317.

Deng, Z. B.; Rong, Y.; Teng, Y.; Mu, J. Y.; Zhuang, X. Y.; Tseng, M.; Samykutty, A.; Zhang, L. F.; Yan, J.; Miller, D. et al. Broccoli-derived nanoparticle inhibits mouse colitis by activating dendritic cell AMP-activated protein kinase. Mol. Ther. 2017, 25, 1641–1654.

Zhang, H. T.; Wang, L.; Li, C. Y.; Yu, Y.; Yi, Y. L.; Wang, J. Y.; Chen, D. P. Exosome-induced regulation in inflammatory bowel disease. Front. Immunol. 2019, 10, 1464.

Sato, T.; Vries, R. G.; Snippert, H. J.; van de Wetering, M.; Barker, N.; Stange, D. E.; van Es, J. H.; Abo, A.; Kujala, P.; Peters, P. J. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009, 459, 262–265.

Snippert, H. J.; van der Flier, L. G.; Sato, T.; van Es, J. H.; van den Born, M.; Kroon-Veenboer, C.; Barker, N.; Klein, A. M.; van Rheenen, J.; Simons, B. D. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 2010, 143, 134–144.

Lamba, M.; Ngu, J. H.; Stedman, C. A. M. Trends in incidence of autoimmune liver diseases and increasing incidence of autoimmune hepatitis. Clin. Gastroenterol. Hepatol. 2021, 19, 573–579.e1.

van der Woude, D.; van der Helm-van Mil, A. H. M. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 2018, 32, 174–187.

Li, J.; Chen, L.; Xu, X. Y.; Fan, Y.; Xue, X.; Shen, M. W.; Shi, X. Y. Targeted combination of antioxidative and anti-inflammatory therapy of rheumatoid arthritis using multifunctional dendrimer-entrapped gold nanoparticles as a platform. Small 2020, 16, e2005661.

Li, Y. F.; Liang, Q. W.; Zhou, L. Y.; Cao, Y. J.; Yang, J. Y.; Li, J.; Liu, J. X.; Bi, J. W.; Liu, Y. H. An ROS-responsive artesunate prodrug nanosystem co-delivers dexamethasone for rheumatoid arthritis treatment through the HIF-1α/NF-κB cascade regulation of ROS scavenging and macrophage repolarization. Acta Biomater. 2022, 152, 406–424.

Chen, X. Y.; Zhou, Y.; Yu, J. J. Exosome-like nanoparticles from ginger rhizomes inhibited NLRP3 inflammasome activation. Mol. Pharm. 2019, 16, 2690–2699.

Feng, Z. T.; Yang, T.; Hou, X. Q.; Wu, H. Y.; Feng, J. T.; Ou, B. J.; Cai, S. J.; Li, J.; Mei, Z. G. Sinomenine mitigates collagen-induced arthritis mice by inhibiting angiogenesis. Biomed. Pharmacother. 2019, 113, 108759.

Chen, J. F.; Wu, W. B.; Zhang, M. M.; Chen, C. M. Taraxasterol suppresses inflammation in IL-1β-induced rheumatoid arthritis fibroblast-like synoviocytes and rheumatoid arthritis progression in mice. Int. Immunopharmacol. 2019, 70, 274–283.

Liang, J.; Chang, B. Y.; Huang, M. C.; Huang, W. C.; Ma, W. K.; Liu, Y.; Tai, W.; Long, Y.; Lu, Y. Oxymatrine prevents synovial inflammation and migration via blocking NF-κB activation in rheumatoid fibroblast-like synoviocytes. Int. Immunopharmacol. 2018, 55, 105–111.

Yu, W. G.; Shen, Y.; Wu, J. Z.; Gao, Y. B.; Zhang, L. X. Madecassoside impedes invasion of rheumatoid fibroblast-like synoviocyte from adjuvant arthritis rats via inhibition of NF-κB-mediated matrix metalloproteinase-13 expression. Chin. J. Nat. Med. 2018, 16, 330–338.

Mateen, S.; Zafar, A.; Moin, S.; Khan, A. Q.; Zubair, S. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin. Chim. Acta 2016, 455, 161–171.

Venkatesan, R.; Xiong, H.; Yao, Y. J.; Reddy Nakkala, J.; Zhou, T.; Li, S. F.; Fan, C. Y.; Gao, C. Y. Immuno-modulating theranostic gold nanocages for the treatment of rheumatoid arthritis in vivo. Chem. Eng. J. 2022, 446, 136868.

Yeh, C. H.; Chen, T. P.; Wu, Y. C.; Lin, Y. M.; Jing Lin, P. Inhibition of NFκB activation with curcumin attenuates plasma inflammatory cytokines surge and cardiomyocytic apoptosis following cardiac ischemia/reperfusion. J. Surg. Res. 2005, 125, 109–116.

Collins, S. M.; Bercik, P. The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 2009, 136, 2003–2014.

Hsu, W. T.; Suen, J. L.; Chiang, B. L. The role of CD4⁺CD25⁺ T cells in autoantibody production in murine lupus. Clin. Exp. Immunol. 2006, 145, 513–519.

Khorasani, S.; Mahmoudi, M.; Kalantari, M. R.; Lavi Arab, F.; Esmaeili, S. A.; Mardani, F.; Tabasi, N.; Rastin, M. Amelioration of regulatory T cells by Lactobacillus delbrueckii and Lactobacillus rhamnosus in pristane-induced lupus mice model. J. Cell Physiol. 2019, 234, 9778–9786.

Salehipour, Z.; Haghmorad, D.; Sankian, M.; Rastin, M.; Nosratabadi, R.; Soltan Dallal, M. M.; Tabasi, N.; Khazaee, M.; Nasiraii, L. R.; Mahmoudi, M. Bifidobacterium animalis in combination with human origin of Lactobacillus plantarum ameliorate neuroinflammation in experimental model of multiple sclerosis by altering CD4+ T cell subset balance. Biomed. Pharmacother 2017, 95, 1535–1548.

Talaat, R. M.; Mohamed, S. F.; Bassyouni, I. H.; Raouf, A. A. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine 2015, 72, 146–153.

Mix, E.; Meyer-Rienecker, H.; Hartung, H. P.; Zettl, U. K. Animal models of multiple sclerosis-potentials and limitations. Prog. Neurobiol. 2010, 92, 386–404.

Suriano, E. S.; Souza, M. D. M.; Kobata, C. M.; Santos, F. H. Y.; Mimica, M. J. Efficacy of an adjuvant Lactobacillus rhamnosus formula in improving skin lesions as assessed by PASI in patients with plaque psoriasis from a university-affiliated, tertiary-referral hospital in São Paulo (Brazil): A parallel, double-blind, randomized clinical trial. Arch. Dermatol. Res. 2023, 315, 1621–1629.

Feng, J. J.; Xiu, Q.; Huang, Y. Y.; Troyer, Z.; Li, B.; Zheng, L. Plant-derived vesicle-like nanoparticles as promising biotherapeutic tools: Present and future. Adv. Mater. 2023, 35, 2207826.

Liu, H.; Li, M. M.; Zhang, T.; Liu, X. R.; Zhang, H.; Geng, Z.; Su, J. C. Engineered bacterial extracellular vesicles for osteoporosis therapy. Chem. Eng. J. 2022, 450, 138309.

Liu, H.; Geng, Z.; Su, J. C. Engineered mammalian and bacterial extracellular vesicles as promising nanocarriers for targeted therapy. Extracell. Vesicles Circ. Nucleic Acids 2022, 3, 63–86.

Zhang, Y. X.; Malzahn, A. A.; Sretenovic, S.; Qi, Y. P. The emerging and uncultivated potential of CRISPR technology in plant science. Nat. Plants 2019, 5, 778–794.

Deng, H.; Huang, W.; Zhang, Z. P. Nanotechnology based CRISPR/Cas9 system delivery for genome editing: Progress and prospect. Nano Res. 2019, 12, 2437–2450.

Demirer, G. S.; Silva, T. N.; Jackson, C. T.; Thomas, J. B.; Ehrhardt, D. W.; Rhee, S. Y.; Mortimer, J. C.; Landry, M. P. Nanotechnology to advance CRISPR-cas genetic engineering of plants. Nat. Nanotechnol. 2021, 16, 243–250.

Cloutier, N.; Paré, A.; Farndale, R. W.; Schumacher, H. R.; Nigrovic, P. A.; Lacroix, S.; Boilard, E. Platelets can enhance vascular permeability. Blood 2012, 120, 1334–1343.

Fuhrmann, G.; Serio, A.; Mazo, M.; Nair, R.; Stevens, M. M. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J. Control. Release 2015, 205, 35–44.

Adriano, B.; Cotto, N. M.; Chauhan, N.; Jaggi, M.; Chauhan, S. C.; Yallapu, M. M. Milk exosomes: Nature's abundant nanoplatform for theranostic applications. Bioact. Mater. 2021, 6, 2479–2490.

Li, S. Y.; Tang, Y.; Dou, Y. S. The potential of milk-derived exosomes for drug delivery. Curr. Drug Deliv. 2021, 18, 688–699.

Umezu, T.; Takanashi, M.; Murakami, Y.; Ohno, S. I.; Kanekura, K.; Sudo, K.; Nagamine, K.; Takeuchi, S.; Ochiya, T.; Kuroda, M. Acerola exosome-like nanovesicles to systemically deliver nucleic acid medicine via oral administration. Mol. Ther. Methods Clin. Dev. 2021, 21, 199–208.

Zhang, M. Z.; Xiao, B.; Wang, H.; Han, M. K.; Zhang, Z.; Viennois, E.; Xu, C. L.; Merlin, D. Edible ginger-derived nano-lipids loaded with doxorubicin as a novel drug-delivery approach for colon cancer therapy. Mol. Ther. 2016, 24, 1783–1796.

Yang, C. H.; Zhang, M. Z.; Lama, S.; Wang, L. X.; Merlin, D. Natural-lipid nanoparticle-based therapeutic approach to deliver 6-shogaol and its metabolites M2 and M13 to the colon to treat ulcerative colitis. J. Control. Release 2020, 323, 293–310.

Ren, X. X.; Chen, X.; Geng, Z.; Su, J. C. Bone-targeted biomaterials: Strategies and applications. Chem. Eng. J. 2022, 446, 137133.

Guo, J. W.; Wang, F. X.; Hu, Y.; Luo, Y.; Wei, Y.; Xu, K.; Zhang, H.; Liu, H.; Bo, L. M.; Lv, S. L. et al. Exosome-based bone-targeting drug delivery alleviates impaired osteoblastic bone formation and bone loss in inflammatory bowel diseases. Cell Rep. Med. 2023, 4, 100881.

Xue, X.; Liu, H.; Wang, S. C.; Hu, Y.; Huang, B. T.; Li, M. M.; Gao, J.; Wang, X. H.; Su, J. C. Neutrophil-erythrocyte hybrid membrane-coated hollow copper sulfide nanoparticles for targeted and photothermal/ anti-inflammatory therapy of osteoarthritis. Compos. B Eng. 2022, 237, 109855.

Wang, L. X.; Qi, C. X.; Cao, H. M.; Zhang, Y. W.; Liu, X.; Qiu, L. N.; Wang, H.; Xu, L. J.; Wu, Z. Z.; Liu, J. F. et al. Engineered cytokine-primed extracellular vesicles with high PD-L1 expression ameliorate type 1 diabetes. Small 2023, in press, DOI: 10.1002/smll.202301019.

Zhou, Y.; Wang, L.; Chen, L. F.; Wu, W.; Yang, Z. M.; Wang, Y. Z.; Wang, A. Q.; Jiang, S. J.; Qin, X. Z.; Ye, Z. C. et al. Glioblastoma cell-derived exosomes functionalized with peptides as efficient nanocarriers for synergistic chemotherapy of glioblastoma with improved biosafety. Nano Res. 2023, in press, DOI: 10.1007/s12274-023-5921-6.

Wang, M. Y.; Wang, Y. F.; Mu, Y. T.; Yang, F. X.; Yang, Z. B.; Liu, Y. X.; Huang, L. L.; Liu, S.; Guan, X. G.; Xie, Z. G. et al. Engineering SIRPα cellular membrane-based nanovesicles for combination immunotherapy. Nano Res. 2023, 16, 7355–7363.

Li, H.; Zhong, Y. F.; Wang, S. M.; Zha, M.; Gu, W. X.; Liu, G. Y.; Wang, B. H.; Yu, Z. D.; Wang, Y.; Li, K. et al. In vivo bioorthogonal labeling of rare-earth doped nanoparticles for improved NIR-II tumor imaging by extracellular vesicle-mediated targeting. Nano Res. 2023, 16, 2904–2895.

Li, D.; Yao, S. R.; Zhou, Z. F.; Shi, J.; Huang, Z. H.; Wu, Z. M. Hyaluronan decoration of milk exosomes directs tumor-specific delivery of doxorubicin. Carbohydr. Res. 2020, 493, 108032.

Niu, W. B.; Xiao, Q.; Wang, X. J.; Zhu, J. Q.; Li, J. H.; Liang, X. M.; Peng, Y. M.; Wu, C. T.; Lu, R. J.; Pan, Y. et al. A biomimetic drug delivery system by integrating grapefruit extracellular vesicles and doxorubicin-loaded heparin-based nanoparticles for glioma therapy. Nano Lett. 2021, 21, 1484–1492.

Headland, S. E.; Jones, H. R.; Norling, L. V.; Kim, A.; Souza, P. R.; Corsiero, E.; Gil, C. D.; Nerviani, A.; Dell'Accio, F.; Pitzalis, C. et al. Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis. Sci. Transl. Med. 2015, 7, 315ra190.

Topping, L. M.; Thomas, B. L.; Rhys, H. I.; Tremoleda, J. L.; Foster, M.; Seed, M.; Voisin, M. B.; Vinci, C.; Law, H. L.; Perretti, M. et al. Targeting extracellular vesicles to the arthritic joint using a damaged cartilage-specific antibody. Front. Immunol. 2020, 11, 10.

Zhang, Q.; Xiao, Q.; Yin, H. L.; Xia, C. W.; Pu, Y. M.; He, Z. F.; Hu, Q. G.; Wang, J. Q.; Wang, Y. X. Milk-exosome based pH/light sensitive drug system to enhance anticancer activity against oral squamous cell carcinoma. RSC Adv. 2020, 10, 28314–28323.

Gao, J. F.; Yakufu, W.; Yang, H. B.; Song, Y. N.; Wang, Q. Z.; Li, Q. Y.; Tan, H. P.; Chen, J.; Sun, D. L.; Wang, Z. M. et al. Early initiation of ARBs without blood pressure risk via neutrophil membrane-fused pH-sensitive liposomes to reduce cardiomyocyte apoptosis after acute myocardial infarction. Nano Res. 2023, 16, 9894–9905.

Wang, Q. L.; Ren, Y.; Mu, J. Y.; Egilmez, N. K.; Zhuang, X. Y.; Deng, Z. B.; Zhang, L. F.; Yan, J.; Miller, D.; Zhang, H. G. Grapefruit-derived nanovectors use an activated leukocyte trafficking pathway to deliver therapeutic agents to inflammatory tumor sites. Cancer Res. 2015, 75, 2520–2529.

Chen, P. F.; Liu, X.; Gu, C. H.; Zhong, P. Y.; Song, N.; Li, M. B.; Dai, Z. Q.; Fang, X. Q.; Liu, Z. M.; Zhang, J. F. et al. A plant-derived natural photosynthetic system for improving cell anabolism. Nature 2022, 612, 546–554.

Yang, J. L.; Zhu, Y.; Wang, F.; Deng, L. F.; Xu, X. Y.; Cui, W. G. Microfluidic liposomes-anchored microgels as extended delivery platform for treatment of osteoarthritis. Chem. Eng. J. 2020, 400, 126004.

Tibbitt, M. W.; Dahlman, J. E.; Langer, R. Emerging frontiers in drug delivery. J. Am. Chem. Soc. 2016, 138, 704–717.

Mao, Y. L.; Han, M. Q.; Chen, C. S.; Wang, X. D.; Han, J. N.; Gao, Y. K.; Wang, S. L. A biomimetic nanocomposite made of a ginger-derived exosome and an inorganic framework for high-performance delivery of oral antibodies. Nanoscale 2021, 13, 20157–20169.

Prausnitz, M. R.; Langer, R. Transdermal drug delivery. Nat. Biotechnol. 2008, 26, 1261–1268.

Gu, T. W.; Wang, M. Z.; Niu, J.; Chu, Y.; Guo, K. R.; Peng, L. H. Outer membrane vesicles derived from E. coli as novel vehicles for transdermal and tumor targeting delivery. Nanoscale 2020, 12, 18965–18977.

Yepes-Molina, L.; Martínez-Ballesta, M. C.; Carvajal, M. Plant plasma membrane vesicles interaction with keratinocytes reveals their potential as carriers. J. Adv. Res. 2020, 23, 101–111.

Zhou, D. Y.; Zhou, F. J.; Sheng, S. H.; Wei, Y.; Chen, X.; Su, J. C. Intra-articular nanodrug delivery strategies for treating osteoarthritis. Drug Discov. Today 2023, 28, 103482.

Xue, X.; Hu, Y.; Deng, Y. H.; Su, J. C. Recent advances in design of functional biocompatible hydrogels for bone tissue engineering. Adv. Funct. Mater. 2021, 31, 2009432.

Zhang, H.; Wu, S. L.; Chen, W. K.; Hu, Y.; Geng, Z.; Su, J. C. Bone/cartilage targeted hydrogel: Strategies and applications. Bioact. Mater. 2023, 23, 156–169.

Pang, L. Y.; Jin, H.; Lu, Z. M.; Xie, F. Y.; Shen, H. X.; Li, X. Y.; Zhang, X. Y.; Jiang, X. H.; Wu, L. L.; Zhang, M. Y. et al. Treatment with mesenchymal stem cell-derived nanovesicle-containing gelatin methacryloyl hydrogels alleviates osteoarthritis by modulating chondrogenesis and macrophage polarization. Adv. Healthc. Mater. 2023, 12, e2300315.

Kim, S. Q.; Kim, K. H. Emergence of edible plant-derived nanovesicles as functional food components and nanocarriers for therapeutics delivery: Potentials in human health and disease. Cells 2022, 11, 2232.

Baglio, S. R.; Pegtel, D. M.; Baldini, N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front. Physiol. 2012, 3, 359.

Zu, M. H.; Xie, D. C.; Canup, B. S. B.; Chen, N. X.; Wang, Y. J.; Sun, R. X.; Zhang, Z.; Fu, Y. M.; Dai, F. Y.; Xiao, B. 'Green' nanotherapeutics from tea leaves for orally targeted prevention and alleviation of colon diseases. Biomaterials 2021, 279, 121178.

Chen, Y. S.; Lin, E. Y.; Chiou, T. W.; Harn, H. J. Exosomes in clinical trial and their production in compliance with good manufacturing practice. Tzu Chi Med. J. 2020, 32, 113–120.