Dendrobium officinale-derived nanovesicles: a natural therapy for comprehensive regulation of angiogenesis, inflammation, and tissue repair to enhance skin wound healing

Abstract

Skin wound healing is a multifaceted biological process involving dynamic interactions among various cells and signaling molecules. Angiogenesis is a key component of this repair process. Dendrobium officinale, a traditional medicinal plant, has shown therapeutic promise, particularly through its bioactive nanovesicles. This study investigates the therapeutic potential of Dendrobium officinale-derived nanovesicles (DDNVs) in regulating angiogenesis, inflammation, and tissue repair, to promote enhanced skin wound healing. A full-thickness mouse skin wound model was used to evaluate the in vivo effects of DDNVs on wound closure, angiogenesis, and collagen remodeling. Histological staining (H&E and Masson’s trichrome) and CD31 immunofluorescence were performed. In vitro, DDNVs were tested on Human umbilical vein endothelial cells(HUVECs) and Human keratinocyte cells (HaCaT) cells to assess cell proliferation, migration, and angiogenesis. Confocal microscopy was used to track cellular uptake. Activation of the Akt/eNOS pathway and expression of key genes related to inflammation and matrix remodeling were evaluated by Western blotting and qPCR. DDNVs significantly accelerated wound healing and promoted angiogenesis in vivo, as evidenced by enhanced CD31 expression and collagen remodeling. In vitro, DDNVs entered cells efficiently and stimulated HUVEC and HaCaT proliferation and migration. This was accompanied by activation of the Akt/eNOS signaling pathway, increased expression of eNOS and VEGFR-2, upregulation of extracellular matrix(ECM) components (Vimentin, Fibronectin, COL1A1), and suppression of inflammatory markers such as ICAM-1 and IL-1β. DDNVs exhibit strong potential to enhance skin wound healing by promoting angiogenesis, improving tissue repair, and modulating inflammation. These findings support the clinical development of DDNVs as a novel, plant-derived nanotherapeutic for chronic wound treatment and skin regeneration.

Keywords

Skin wound healing / Angiogenesis / Plant-derived nanovesicles / AKT/eNOS

References

[1] AbrahamAM, WiemannS, AmbreenG, ZhouJ, EngelhardtK, BrüßlerJ, BakowskyU, LiSM, MandicR, PocsfalviG, KeckCM. Cucumber-Derived Exosome-like vesicles and plantcrystals for improved dermal drug delivery. Pharmaceutics, 2022, 143476.

[2] BahriF, MansooriM, VafaeiS, FooladiS, MirY, MehrabaniM, HozhabriY, NematollahiMH, IravaniS. A comprehensive review on ginger-derived exosome-like nanoparticles as feasible therapeutic nano-agents against diseases. Mater Adv, 2024, 5(5): 1846-1867.

[3] Berry-KilgourC, CabralJ, WiseL. Advancements in the delivery of growth factors and cytokines for the treatment of cutaneous wound indications. Adv Wound Care, 2021, 10(11): 596-622.

[4] BurgessJL, WyantWA, AbujamraA, KirsnerB, JozicI. Diabetic Wound-Healing science. Med (Kaunas Lithuania), 2021, 57101072.

[5] CaoM, DiaoN, CaiX, ChenX, XiaoY, GuoC, ChenD, ZhangX. Plant exosome nanovesicles (PENs): green delivery platforms. Mater Horiz, 2023, 10(10): 3879-3894.

[6] ChaoYH, YangWT, LiMC, YangFL, LeeRP. Angelica Dahurica and Rheum officinale facilitated diabetic wound healing by elevating vascular endothelial growth factor. Am J Chin Med, 2021, 49(6): 1515-1533.

[7] ChenWT, LuoY, ChenXM, XiaoJH. Role of exosome-derived MiRNAs in diabetic wound angiogenesis. Mol Cell Biochem, 2024, 479(10): 2565-2580.

[8] DanielloV, De LeoV, LasalviaM, HossainMN, CarboneA, CatucciL, ZefferinoR, IngrossoC, ConeseM, GioiaD. Solanum lycopersicum (Tomato)-Derived nanovesicles accelerate wound healing by eliciting the migration of keratinocytes and fibroblasts. Int J Mol Sci, 2024, 2552452.

[9] de la Torre-EscuderoE, RobinsonMW. Extracellular vesicle-mediated communication in host-parasite interactions: insight from Fasciola hepatica. Annals Translational Med, 2017, 5Suppl 1S8.

[10] Fan R, Zhang C, Li F, Li B, McCarthy A, Zhang Y, Chen S, Zhang L (2024) Hierarchically assembled nanofiber scaffolds with dual growth factor gradients promote skin wound healing through rapid cell recruitment. Advanced Science (Weinheim,Baden-Wurttemberg,Germany) 11(14):e2309993. https://doi.org/10.1002/advs.202309993

[11] HeH, HuangW, ZhangS, LiJ, ZhangJ, LiB, XuJ, LuoY, ShiH, LiY, XiaoJ, EzekielOC, LiX, WuJ. Microneedle patch for transdermal sequential delivery of KGF-2 and aFGF to enhance burn wound therapy. Small (Weinheim an der Bergstrasse. Germany), 2024, 2034e2307485.

[12] HouJ, WeiW, GengZ, ZhangZ, YangH, ZhangX, LiL, GaoQ. Developing plant exosomes as an advanced delivery system for cosmetic peptide. ACS Appl Bio Mater, 2024, 7(5): 3050-3060.

[13] HuangR, JiaB, SuD, LiM, XuZ, HeC, HuangY, FanH, ChenH, ChengF. Plant exosomes fused with engineered mesenchymal stem cell-derived nanovesicles for synergistic therapy of autoimmune skin disorders. J Extracell Vesicles, 2023, 1210e12361.

[14] KangN, GaoH, HeL, LiuY, FanH, XuQ, YangS. Ginsenoside Rb1 is an immune-stimulatory agent with antiviral activity against enterovirus 71. J Ethnopharmacol, 2021, 266113401.

[15] KaramanS, LeppänenVM, AlitaloK. Vascular endothelial growth factor signaling in development and disease. Development, 2018, 14514dev151019.

[16] KimK, ParkJ, SohnY, OhCE, ParkJH, YukJM, YeonJH. Stability of plant Leaf-Derived extracellular vesicles according to preservative and storage temperature. Pharmaceutics, 2022, 142457.

[17] LiL, YaoDN, LuY, DengJW, WeiJA, YanYH, DengH, HanL, LuCJ. Metabonomics study on serum characteristic metabolites of psoriasis vulgaris patients with Blood-Stasis syndrome. Front Pharmacol, 2020, 11558731.

[18] LiA, LiD, GuY, LiuR, TangX, ZhaoY, QiF, WeiJ, LiuJ. Plant-derived nanovesicles: further exploration of biomedical function and application potential. Acta Pharm Sinica B, 2023, 13(8): 3300-3320.

[19] LiuH, LiangJ, ZhongY, XiaoG, EfferthT, GeorgievMI, Vargas-De-La-CruzC, BajpaiVK, CaprioliG, LiuJ, LinJ, WuH, PengL, LiY, MaL, XiaoJ, WangQ. Dendrobium officinale polysaccharide alleviates intestinal inflammation by promoting small extracellular vesicle packaging of miR-433-3p. J Agric Food Chem, 2021, 69(45): 13510-13523.

[20] LoKJ, WangMH, HoCT, PanMH. Plant-Derived extracellular vesicles: A new revolutionization of modern healthy diets and biomedical applications. J Agric Food Chem, 2024, 72(6): 2853-2878.

[21] NematiM, SinghB, MirRA, NematiM, BabaeiA, AhmadiM, RasmiY, GolezaniAG, RezaieJ. Plant-derived extracellular vesicles: a novel nanomedicine approach with advantages and challenges. Cell Communication Signaling: CCS, 2022, 20169.

[22] PeñaOA, MartinP. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol, 2024, 25(8): 599-616.

[23] PomattoMAC, GaiC, NegroF, MassariL, DeregibusMC, De RosaFG, CamussiG. Oral delivery of mRNA vaccine by Plant-Derived extracellular vesicle carriers. Cells, 2023, 12141826.

[24] Saroj S, Saha S, Ali A, Gupta SK, Bharadwaj A, Agrawal T, Pal S, Rakshit T (2025) Plant Extracellular Nanovesicle-Loaded Hydrogel for Topical Antibacterial Wound Healing In Vivo. ACS Applied Bio Materials:8(1) 1–11. https://doi.org/10.1021/acsabm.4c00992

[25] SinghM, ThakurV, KumarV, RajM, GuptaS, DeviN, UpadhyaySK, MachoM, BanerjeeA, EweD, SauravK. Silver nanoparticles and its mechanistic insight for chronic wound healing: review on recent progress. Molecules, 2022, 27175587.

[26] SongY, KongH, OhS, KimSB. Plant-derived extracellular vesicles as nanocarriers for combination therapy enhancing paclitaxel-based regimens in breast cancer. BMB Rep, 2025, 58(2): 53-63.

[27] StarkRJ, KochSR, ChoiH, MaceEH, DikalovSI, SherwoodER, LambFS. Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling. FASEB Journal: Official Publication Federation Am Soc Experimental Biology, 2018, 32(2): 945-956.

[28] SuCY, LiuTY, WangHV, YangWC. Histopathological study on collagen in Full-Thickness wound healing in fraser’s dolphins (Lagenodelphis hosei). Animals: Open Access J MDPI, 2023, 13101681.

[29] SubhaD, AnuKiruthikaR, SreerajH, TamilselviKS. Plant exosomes: nano conveyors of pathogen resistance. Discover Nano, 2023, 181146.

[30] TanM, LiuY, XuY, YanG, ZhouN, ChenH, JiangZ, PengL. Plant-Derived exosomes as novel nanotherapeutics contrive Glycolysis Reprogramming-Mediated angiogenesis for diabetic ulcer healing. Biomaterials Res, 2024, 280035.

[31] TanS, LiuZ, CongM, ZhongX, MaoY, FanM, JiaoF, QiaoH. Dandelion-derived vesicles-laden hydrogel dressings capable of neutralizing Staphylococcus aureus exotoxins for the care of invasive wounds. J Controlled Release: Official J Controlled Release Soc, 2024, 368: 355-371.

[32] TuJ, JiangF, FangJ, XuL, ZengZ, ZhangX, BaL, LiuH, LinF. Anticipation and verification of Dendrobium-Derived nanovesicles for skin wound healing targets, predicated upon immune infiltration and senescence. Int J Nanomed, 2024, 19: 1629-1644.

[33] WangC, ZhangZ, XuT, LouY, WangQ, JinH, ZhangL, FengY, XuH, MaoC. Upregulating mTOR/ERK signaling with leonurine for promoting angiogenesis and tissue regeneration in a full-thickness cutaneous wound model. Food Funct, 2018, 9(4): 2374-2385.

[34] WangS, YangJ, ZhaoG, LiuR, DuY, CaiZ, LuanJ, ShenY, ChenB. Current applications of platelet gels in wound healing-A review. Wound Repair Regeneration: Official Publication Wound Healing Soc [and] Eur Tissue Repair Soc, 2021, 29(3): 370-379.

[35] WangY, ChuF, LinJ, LiY, JohnsonN, ZhangJ, GaiC, SuZ, ChengH, WangL, DingX. Erianin, the main active ingredient of Dendrobium chrysotoxum lindl, inhibits precancerous lesions of gastric cancer (PLGC) through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network Pharmacology and in vitro experimental verification. J Ethnopharmacol, 2021, 279114399.

[36] WangH, MuJ, ChenY, LiuY, LiX, LiH, CaoP. Hybrid Ginseng-derived extracellular Vesicles-Like particles with autologous tumor cell membrane for personalized vaccination to inhibit tumor recurrence and metastasis. Advanced science (Weinheim, Baden-Wurttemberg. Germany), 2024, 1117e2308235.

[37] XuTY, QingSL, ZhaoJX, SongJ, MiaoZW, LiJX, YangFY, ZhaoHY, ZhengSL, LiZY, WangSN, MiaoCY. Metrnl deficiency retards skin wound healing in mice by inhibiting akt/enos signaling and angiogenesis. Acta Pharmacol Sin, 2023, 44(9): 1790-1800.

[38] YangR, LinF, WangW, DaiG, KeX, WuG. Investigating the therapeutic effects and mechanisms of Carthamus tinctorius L.-derived nanovesicles in atherosclerosis treatment. Cell Communication Signaling: CCS, 2024, 221178.

[39] YuM, LiuW, LiJ, LuJ, LuH, JiaW, LiuF. Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via akt/enos pathway. Stem Cell Res Ther, 2020, 111350.

[40] ZhaoQ, WangT, WangH, CaoP, JiangC, QiaoH, PengL, LinX, JiangY, JinH, ZhangH, WangS, WangY, WangY, ChenX, FanJ, LiB, LiG, LiuB, LiZ, ZhaoK. Consensus statement on research and application of Chinese herbal medicine derived extracellular vesicles-like particles (2023 edition). Chin Herb Med, 2023, 16(1): 3-12.

[41] ZuoSM, YuHD, ZhangW, ZhongQ, ChenW, ChenW, YunYH, ChenH. Comparative metabolomic analysis of Dendrobium officinale under different cultivation substrates. Metabolites, 2020, 108325.

[42] ZuzarteM, VitorinoC, SalgueiroL, GirãoH. Plant nanovesicles for essential oil delivery. Pharmaceutics, 2022, 14122581.

Funding

Natural Science Foundation of Guangdong Province(2022A1515011710)

RIGHTS & PERMISSIONS

The Author(s)