# Harnessing the Therapeutic Potential of Extracellular Vesicles for Oral Wound Healing

**Authors:** Helly A. Patel, Bianca Schmiliver, Keerthi Priya Chinniyampalayam Sekar, Mirelle Dogini, Chidubem Onyeagoro, Daniel C. Shah, M. Hope Robinson, Babatunde Giwa-Otusajo, David T. Wu, Steven L. Goudy

PMC · DOI: 10.3390/bioengineering13020148 · Bioengineering · 2026-01-27

## TL;DR

This review explores how extracellular vesicles can be used as a safe and effective treatment for oral wounds, offering an alternative to traditional cell-based therapies.

## Contribution

The paper provides a comprehensive overview of extracellular vesicle sources, engineering, and delivery methods for oral wound healing.

## Key findings

- Extracellular vesicles offer a cell-free alternative with reduced risks compared to cell-based therapies.
- EVs can be engineered and delivered using advanced platforms like hydrogels and microneedles.
- Oral wound healing differs from cutaneous healing, requiring tailored therapeutic approaches.

## Abstract

Oral wound healing is a robust process; however, complications from surgery, systemic diseases, and aging can impair healing. While some treatments exist, regenerative therapies to promote mucosal wound healing remain limited. In recent years, there has been a significant rise in FDA-approved cell-based therapies; however, extracellular vesicles represent an emerging cell-free alternative that may mitigate risks associated with cellular therapies, including tumorigenesis and immunogenicity. These lipid-encapsulated nanovesicles can deliver therapeutic cargo, such as proteins, lipids, nucleic acids, or drugs, to the wound site. Extracellular vesicles can be derived from mesenchymal stromal cells, immune cells, bodily fluids, or bacteria, and engineered through genetic modification, preconditioning, or direct cargo loading to enhance therapeutic potency. Furthermore, advanced delivery platforms, including hydrogels, microneedles, and aerosols, allow for sustained and localized EV delivery to the oral wound site. This review examines differences between cutaneous and oral wound healing; factors that impair oral repair; extracellular vesicle sources and engineering strategies; and delivery strategies for developing EV-based therapeutics for oral wound healing.

## Full-text entities

- **Genes:** CD9 (CD9 molecule) [NCBI Gene 928] {aka BTCC-1, DRAP-27, MIC3, MRP-1, TSPAN-29, TSPAN29}, MMP3 (matrix metallopeptidase 3) [NCBI Gene 4314] {aka CHDS6, MMP-3, SL-1, STMY, STMY1, STR1}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, CD63 (CD63 molecule) [NCBI Gene 967] {aka AD1, HOP-26, ME491, MLA1, OMA81H, Pltgp40}, SOX2 (SRY-box transcription factor 2) [NCBI Gene 6657] {aka ANOP3, MCOPS3}, CXCL10 (C-X-C motif chemokine ligand 10) [NCBI Gene 615107], AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, Prrx1 (paired related homeobox 1) [NCBI Gene 18933] {aka A230024N07Rik, K-2, MHox1, Pmx, Pmx1, Prx1}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, ANG (angiogenin) [NCBI Gene 283] {aka ALS9, HEL168, RAA1, RNASE4, RNASE5}, CD81 (CD81 molecule) [NCBI Gene 975] {aka CVID6, S5.7, TAPA1, TSPAN28}, MIR199A2 (microRNA 199a-2) [NCBI Gene 406977] {aka MIR-199-s, MIRN199A2, mir-199a-2}, CTSS (cathepsin S) [NCBI Gene 1520], Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 25125], TSG101 (tumor susceptibility 101) [NCBI Gene 7251] {aka TSG10, VPS23}, COL2A1 (collagen type II alpha 1 chain) [NCBI Gene 1280] {aka ACG2, ANFH, ANFH1, AOM, COL11A3, EDMMD}, Smad3 (SMAD family member 3) [NCBI Gene 17127] {aka Madh3}, GJA1 (gap junction protein alpha 1) [NCBI Gene 281193] {aka CXNK1}, TLR3 (toll like receptor 3) [NCBI Gene 7098] {aka CD283, IIAE2, IMD83}, IL4 (interleukin 4) [NCBI Gene 280824] {aka BSF-1, IL-4}, Mrc1 (mannose receptor, C type 1) [NCBI Gene 17533] {aka CD206, MR}, BMP2 (bone morphogenetic protein 2) [NCBI Gene 650] {aka BDA2, BMP2A, SSFSC, SSFSC1}, Cd80 (CD80 antigen) [NCBI Gene 12519] {aka B71, Cd28l, Ly-53, Ly53, MIC17, TSA1}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, UBE2O (ubiquitin conjugating enzyme E2 O) [NCBI Gene 63893] {aka E2-230K}, MMP1 (matrix metallopeptidase 1) [NCBI Gene 4312] {aka CLG}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, EGF (epidermal growth factor) [NCBI Gene 1950] {aka HOMG4, URG}, LIF (LIF interleukin 6 family cytokine) [NCBI Gene 280840], TAB2 (TGF-beta activated kinase 1 (MAP3K7) binding protein 2) [NCBI Gene 23118] {aka CHTD2, MAP3K7IP2, TAB-2}, MAP2K2 (mitogen-activated protein kinase kinase 2) [NCBI Gene 5605] {aka CFC4, MAPKK2, MEK2, MKK2, PRKMK2}, Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, PTEN (phosphatase and tensin homolog) [NCBI Gene 5728] {aka 10q23del, BZS, CWS1, DEC, GLM2, MHAM}, RIPK2 (receptor interacting serine/threonine kinase 2) [NCBI Gene 8767] {aka CARD3, CARDIAK, CCK, GIG30, RICK, RIP2}, YAP1 (Yes1 associated transcriptional regulator) [NCBI Gene 10413] {aka COB1, YAP, YAP-1, YAP2, YAP65, YKI}, Jak2 (Janus kinase 2) [NCBI Gene 24514], Vcan (versican) [NCBI Gene 13003] {aka 5430420N07Rik, 9430051N09, Cspg2, DPEAAE, PG-M, PG-M(V0)}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, PITX1 (paired like homeodomain 1) [NCBI Gene 5307] {aka BFT, CCF, POTX, PTX1}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, PDCD6IP (programmed cell death 6 interacting protein) [NCBI Gene 10015] {aka AIP1, ALIX, DRIP4, HP95, MCPH29}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, COL1A1 (collagen type I alpha 1 chain) [NCBI Gene 1277] {aka CAFYD, EDSARTH1, EDSC, OI1, OI2, OI3}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, ITGB1 (integrin subunit beta 1) [NCBI Gene 3688] {aka CD29, FNRB, GPIIA, MDF2, MSK12, VLA-BETA}, NOD2 (nucleotide binding oligomerization domain containing 2) [NCBI Gene 64127] {aka ACUG, BLAU, BLAUS, CARD15, CD, CLR16.3}, MRC1 (mannose receptor C-type 1) [NCBI Gene 4360] {aka CD206, CLEC13D, CLEC13DL, MMR, MRC1L1, bA541I19.1}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, SMAD6 (SMAD family member 6) [NCBI Gene 4091] {aka AOVD2, HsT17432, MADH6, MADH7}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, MIR21 (microRNA 21) [NCBI Gene 406991] {aka MIRN21, hsa-mir-21, miR-21, miRNA21}, MIR215 (microRNA 215) [NCBI Gene 406997] {aka MIRN215, miRNA215, mir-215}, F2 (coagulation factor II, thrombin) [NCBI Gene 2147] {aka PT, RPRGL2, THPH1}, Trem1 (triggering receptor expressed on myeloid cells 1) [NCBI Gene 58217], SPRR1B (small proline rich protein 1B) [NCBI Gene 6699] {aka CORNIFIN, GADD33, SPR-IB, SPRR1}, WNT5A (Wnt family member 5A) [NCBI Gene 7474] {aka hWNT5A}
- **Diseases:** oral pain (MESH:D010146), injury to (MESH:D014947), Inflammation (MESH:D007249), periodontitis (MESH:D010518), complications (MESH:D008107), fibrosis (MESH:D005355), inflamed (MESH:C531841), hyperglycemia (MESH:D006943), head and neck cancer (MESH:D006258), dysbiosis (MESH:D064806), necrotic bone (MESH:D010020), diabetes (MESH:D003920), Sjogren's syndrome (MESH:D012859), Milk (MESH:D016269), tumorigenesis (MESH:D063646), oral mucosal lesions (MESH:D009059), autoimmune conditions (MESH:D001327), Hypoxic (MESH:D002534), bleeding (MESH:D006470), burns (MESH:D002056), systemic disease (MESH:D034721), hypoxia (MESH:D000860), alveolar (MESH:D002282), ischemia (MESH:D007511), tongue ulcer (MESH:D014060), cleft lip and palate (MESH:D002971), bone loss (MESH:D001847), oral mucositis (MESH:D013280), ulcers (MESH:D014456), insulin resistance (MESH:D007333), cleft palate (MESH:D002972), infected (MESH:D007239), nasal regurgitation (MESH:D009668), dental injury (MESH:D009057), salivary dysfunction (MESH:D012466), candidiasis (MESH:D002177), peri-implantitis lesions (MESH:D057873), EV (MESH:D004819), bacterial infections (MESH:D001424), xerostomia (MESH:D014987), mucositis (MESH:D052016), ulcerative colitis (MESH:D003093), HIV infection (MESH:D015658), periodontal disease (MESH:D010510), ONF (MESH:D005402), necrosis (MESH:D009336)
- **Chemicals:** chitosan (MESH:D048271), alginate (MESH:D000464), oxygen (MESH:D010100), methionine (MESH:D008715), reuterin (MESH:C047158), polymer (MESH:D011108), polysaccharides (MESH:D011134), PEG (MESH:D011092), water (MESH:D014867), VH298 (MESH:C000628165), hyaluronic acid (MESH:D006820), ceramide (MESH:D002518), H2O2 (MESH:D006861), DPSC (-), sphingomyelin (MESH:D013109), PCL (MESH:C016240), LPS (MESH:D008070), PLA (MESH:C033616), lipid (MESH:D008055), Saponin (MESH:D012503), ROS (MESH:D017382), methacrylate (MESH:D008689), cellulose (MESH:D002482)
- **Species:** Treponema denticola (species) [taxon 158], Adeno-associated virus (species) [taxon 272636], Streptococcus mutans (species) [taxon 1309], Lacticaseibacillus rhamnosus GG (strain) [taxon 568703], Mus musculus (house mouse, species) [taxon 10090], Enterococcus faecalis (species) [taxon 1351], Lactobacillus acidophilus (species) [taxon 1579], Human immunodeficiency virus 1 (no rank) [taxon 11676], Porphyromonas gingivalis (species) [taxon 837], Tannerella forsythia (species) [taxon 28112], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Fusobacterium nucleatum (species) [taxon 851], Bos taurus (bovine, species) [taxon 9913], Limosilactobacillus reuteri (species) [taxon 1598], Lactiplantibacillus plantarum (species) [taxon 1590]
- **Cell lines:** RAW 264.7 — Mus musculus (Mouse), Mouse leukemia, Cancer cell line (CVCL_0493), umbilical vein endothelial — Homo sapiens (Human), Finite cell line (CVCL_3722)

## Full text

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## Figures

6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12938558/full.md

## References

265 references — full list in the complete paper: https://tomesphere.com/paper/PMC12938558/full.md

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Source: https://tomesphere.com/paper/PMC12938558