# Extracellular vesicles conjugated with c(RGDyk) peptide targeting integrin αVβ3 repair optic nerve injury through YAP/TAZ and Smad2/3 signaling **Authors:** Mira Park, Hyun Ah Shin, Hey Jin Lee, Jong Hyun Moon, Jun Yong Kim, Won-Kyu Rhim, Dong Keun Han, Helen Lew PMC · DOI: 10.1093/stcltm/szag006 · Stem Cells Translational Medicine · 2026-02-27 ## TL;DR This study shows that extracellular vesicles modified with a specific peptide can better target and repair optic nerve injuries by activating key signaling pathways. ## Contribution The novel use of c(RGDyk) peptide-conjugated EVs to enhance targeting and neuroregeneration in optic nerve injury is presented. ## Key findings - c(RGDyK)_EVs showed superior targeting and neuroregeneration in hypoxic and inflammatory models. - Single-cell RNA-seq revealed regulation of RGC regeneration and inflammation via the Yap-Taz pathway. - c(RGDyK)_EVs demonstrated enhanced therapeutic potential compared to unmodified EVs. ## Abstract Extracellular vesicles (EVs) derived from mesenchymal stem cells have therapeutic potential for optic nerve injury. However, further investigations are needed to increase their efficacy. In this study, we tried to enhance targeting and recovery function of EVs using conjugation with integrin αVβ3 antagonist-c(RGDyk) peptide. The molecular mechanism of neuronal repair was investigated as a potential treatment for optic nerve injury. EVs were shown to restore effectively the abnormal regulations of neuronal markers in optic nerve injury models. Notably, the functionally optimized c(RGDyK)_EVs exhibited superior targeting capabilities and modulated neuroregeneration in cases of hypoxic damage and inflammation. Single-cell RNA-seq analysis of R28 cells revealed significant regulation of transcription of genes involved in retinal ganglion cell (RGC) regeneration, neuronal growth, and inflammation by c(RGDyK)_EVs via the Yap-Taz signaling pathway. This study highlighted the enhanced therapeutic potential of c(RGDyK)_EVs over naïve EVs in the context of optic nerve disease. The findings suggested that c(RGDyK)_EVs hold promise as an alternative therapy for optic nerve injury. Graphical Abstract ## Linked entities - **Genes:** YAP1 (Yes1 associated transcriptional regulator) [NCBI Gene 10413], TAFAZZIN (tafazzin, phospholipid-lysophospholipid transacylase) [NCBI Gene 6901], SMAD2 (SMAD family member 2) [NCBI Gene 4087], SMAD3 (SMAD family member 3) [NCBI Gene 4088] ## Full-text entities - **Genes:** Hmgb2l1 (high mobility group box 2-like 1) [NCBI Gene 498072] {aka HMG2, RGD1564519}, Gap43 (growth associated protein 43) [NCBI Gene 29423] {aka Basp2}, Ankrd1 (ankyrin repeat domain 1) [NCBI Gene 27064] {aka Alrp, Carp, Crap, MARP}, Tgfb2 (transforming growth factor, beta 2) [NCBI Gene 81809] {aka TGF-B2}, Fam162a (family with sequence similarity 162, member A) [NCBI Gene 360721], Cd63 (Cd63 molecule) [NCBI Gene 29186], Wnt2 (Wnt family member 2) [NCBI Gene 114487] {aka Wnt}, Stx12 (syntaxin 12) [NCBI Gene 65033] {aka Syn13}, Tafazzin (tafazzin, phospholipid-lysophospholipid transacylase) [NCBI Gene 363521] {aka Taz}, Hif1a (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 29560] {aka HIF1-alpha, MOP1}, Id1 (inhibitor of DNA binding 1) [NCBI Gene 25261] {aka ID125A, Idb1}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 83785] {aka VEGF-A, VEGF111, VEGF164, VPF, Vegf}, Tlr4 (toll-like receptor 4) [NCBI Gene 29260], Pou4f1 (POU class 4 homeobox 1) [NCBI Gene 114503] {aka Brn3a, brn-3A}, Mfn2 (mitofusin 2) [NCBI Gene 64476] {aka HSG}, Oscp1 (organic solute carrier partner 1) [NCBI Gene 362595] {aka RGD1306596}, Ccn1 (cellular communication network factor 1) [NCBI Gene 83476] {aka Cyr61}, Il17a (interleukin 17A) [NCBI Gene 301289] {aka CTLA-8, IL-17, IL-17A, Il17}, Wnt3a (Wnt family member 3A) [NCBI Gene 303181], Nfasc (neurofascin) [NCBI Gene 116690] {aka NF}, Actb (actin, beta) [NCBI Gene 81822] {aka Actx}, Csnk1a1 (casein kinase 1, alpha 1) [NCBI Gene 113927] {aka CK1}, Rbpms (RNA binding protein, mRNA processing factor) [NCBI Gene 498642] {aka RBP-MS, RGD1561067}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 59086] {aka Tgfb}, Rbfox3 (RNA binding fox-1 homolog 3) [NCBI Gene 287847] {aka Hrnbp3, Neun, RGD1560070}, Jun (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 24516], Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, Prdx2 (peroxiredoxin 2) [NCBI Gene 29338] {aka Tdpx1}, Yap1 (Yes1 associated transcriptional regulator) [NCBI Gene 363014] {aka YAP65, Yap}, Bdnf (brain-derived neurotrophic factor) [NCBI Gene 24225], Ctnnb1 (catenin beta 1) [NCBI Gene 84353] {aka Catnb}, Egr1 (early growth response 1) [NCBI Gene 24330] {aka Krox-24, NGFI-A, Ngf1, Ngfi, zif-268}, Smad3 (SMAD family member 3) [NCBI Gene 25631] {aka Madh3, Smad 3, mad3}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 287362] {aka Cias1}, Aif1 (allograft inflammatory factor 1) [NCBI Gene 29427] {aka BART-1, Bart1, iba1, mrf-1}, Cd9 (CD9 molecule) [NCBI Gene 24936], Gfap (glial fibrillary acidic protein) [NCBI Gene 24387], Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa}, Tead1 (TEA domain transcription factor 1) [NCBI Gene 361630] {aka TEF-1}, Icam1 (intercellular adhesion molecule 1) [NCBI Gene 25464] {aka CD54, ICAM, RICAM-I}, Cd81 (Cd81 molecule) [NCBI Gene 25621] {aka Tapa1}, Smad2 (SMAD family member 2) [NCBI Gene 29357] {aka Madh2}, Cryab (crystallin, alpha B) [NCBI Gene 25420] {aka AACRYA}, Tsg101 (tumor susceptibility 101) [NCBI Gene 292925] {aka Rw} - **Diseases:** tissue damage (MESH:D017695), nerve damage (MESH:D000080902), ischemic injury (MESH:D017202), retinal inflammation (MESH:D012173), Hypoxic (MESH:D002534), OS (MESH:C567932), ischemia (MESH:D007511), hypoxia (MESH:D000860), optic nerve disease (MESH:D009901), fibrosis (MESH:D005355), ONI (MESH:D007249), Optic nerve injury (MESH:D020221), optic nerve crush (MESH:D000080344), neurodegenerative diseases (MESH:D019636), ONC (MESH:D009408), vision impairment or loss (MESH:D014786), cancer (MESH:D009369) - **Chemicals:** bicinchoninic acid (MESH:C047117), Zoletil (MESH:C006131), nai (MESH:D012974), sucrose (MESH:D013395), PFA (MESH:C003043), LPS (MESH:D008070), PVDF (MESH:C024865), Tween 20 (MESH:D011136), PBS (MESH:D007854), eosin (MESH:D004801), CoCl2 (MESH:C018021), H&E (MESH:D006371), TFF (MESH:C003726), Cy5.5 azide (-), hematoxylin (MESH:D006416), RGD (MESH:C047981), amine (MESH:D000588), uranyl acetate (MESH:C005460), D2O (MESH:D017666), proparacaine hydrochloride (MESH:C005717), Alexa Fluor 555 (MESH:C000608607), SDS (MESH:D012967), Formvar (MESH:C013215), copper (MESH:D003300), SC (MESH:D012538), ethanol (MESH:D000431), saline (MESH:D012965), Paraffin (MESH:D010232), gadolinium acetate (MESH:C060927), azide (MESH:D001386), Rompun (MESH:D014991), Cy-5.5 (MESH:C098793), c (MESH:D002244), Triton X-100 (MESH:D017830) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Rhodopseudomonas faecalis (species) [taxon 99655], Salmonella enterica subsp. enterica serovar Typhimurium (no rank) [taxon 90371], Mus musculus (house mouse, species) [taxon 10090] - **Cell lines:** R28 — Rattus norvegicus (Rat), Transformed cell line (CVCL_D502), CCD-986SK — Homo sapiens (Human), Finite cell line (CVCL_2400), RKK12 — Mus musculus (Mouse), Hybridoma (CVCL_J992) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12948935/full.md ## Figures 6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12948935/full.md ## References 39 references — full list in the complete paper: https://tomesphere.com/paper/PMC12948935/full.md --- Source: https://tomesphere.com/paper/PMC12948935