Exosome-based therapies for corneal disorders: current status and future perspectives

Ningjing Tang , Xiya Yin , Andrew J.W. Huang , Jian-Xing Ma , Anthony Atala , Yuanyuan Zhang

MedScience ››

PDF (3984KB)
MedScience ›› DOI: 10.1007/s11684-026-1225-z
REVIEW
Exosome-based therapies for corneal disorders: current status and future perspectives
Author information +
History +
PDF (3984KB)

Abstract

Exosomes, extracellular vesicles packed with diverse bioactive molecules, show significant promise as therapeutic agents for corneal disorders. This review provides an overview of the current landscape and future outlook of exosome-based therapies in ophthalmology, with a focus on corneal disease. We summarize the fundamental biology and characteristics of corneal exosomes and discuss their roles in maintaining corneal homeostasis and driving disease processes. The therapeutic potential of exosomes in corneal ulcers, dry eye disease (DED), scarring, and dystrophies is evaluated, highlighting preclinical evidence that exosomes can promote epithelial wound healing, modulate inflammation and fibrosis, and support tissue regeneration, as well as emerging clinical studies that begin to assess their safety and feasibility. We also address critical aspects of exosome isolation, characterization, engineering, and delivery strategies that are relevant for clinical translation. Despite encouraging preclinical findings, significant challenges remain, particularly in standardizing manufacturing and quality control, ensuring safety, and achieving consistent therapeutic efficacy. Future research should focus on optimizing exosome production and delivery, rationally engineering them to enhance therapeutic performance, and exploring their potential as biomarkers. Overall, exosome-based therapies hold substantial promise for transforming the management of corneal diseases, but further rigorous translational and clinical studies are required to realize their full potential.

Keywords

exosomes / corneal disorders / therapeutics / extracellular vesicles / regenerative medicine

Cite this article

Download citation ▾
Ningjing Tang, Xiya Yin, Andrew J.W. Huang, Jian-Xing Ma, Anthony Atala, Yuanyuan Zhang. Exosome-based therapies for corneal disorders: current status and future perspectives. MedScience DOI:10.1007/s11684-026-1225-z

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

DelMonte DW , Kim T . Anatomy and physiology of the cornea. J Cataract Refract Surg 2011; 37(3): 588–598

[2]

Fernandez EJ , Bueno JM . Quantitative characterization of corneal collagen architecture using intensity gradient modeling and gaussian PDF fitting. Diagnostics (Basel) 2025; 15(14): 1738

[3]

Sanches JM , Ayilam Ramachandran R , Mussi N , Baniasadi HR , Robertson DM . IL-1β-mediated immunometabolic adaptation in corneal epithelial cells. J Inflamm Res 2025; 18: 9537–9555

[4]

Friedrich M , Lind J , Son HS , Yildirim TM , Auffarth GU , Augustin VA . Visual and ultrastructural analysis after splitting of recipient’s Descemet membrane during Descemet membrane endothelial keratoplasty. Eye (Lond) 2025; 39(11): 2307–2313

[5]

Hu X , Liu R , Zhang C , Wang Y , Wei R , Kong B , Zhou X , Li M . Human corneal lenticules decorated with mesenchymal-stem-cells-encapsulated microneedles for cornea stroma regeneration. ACS Nano 2025; 19(29): 26500–26513

[6]

GBD 2019 Blindness , Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden of Disease Study . Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the right to sight—an analysis for the Global Burden of Disease Study. Lancet Glob Health 2021; 9(2): e144–e160

[7]

Wang EY , Kong X , Wolle M , Gasquet N , Ssekasanvu J , Mariotti SP , Bourne R , Taylor H , Resnikoff S , West S . Global trends in blindness and vision impairment resulting from corneal opacity 1984–2020: a meta-analysis. Ophthalmology 2023; 130(8): 863–871

[8]

Ting DSJ , Ho CS , Deshmukh R , Said DG , Dua HS . Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance. Eye (Lond) 2021; 35(4): 1084–1101

[9]

Asheim C , Puri A , Song H , Armstrong B , Navon S , Krueger R . The Nebraska Nomogram for Autograft Planning (NNAP) a surgical planning tool for ipsilateral rotational autokeratoplasty. NPJ Digit Med 2025; 8(1): 330

[10]

Mohan RR , Kempuraj D , D’Souza S , Ghosh A . Corneal stromal repair and regeneration. Prog Retin Eye Res 2022; 91: 101090

[11]

Gain P , Jullienne R , He Z , Aldossary M , Acquart S , Cognasse F , Thuret G . Global survey of corneal transplantation and eye banking. JAMA Ophthalmol 2016; 134(2): 167–173

[12]

Alio JL , Montesel A , El Sayyad F , Barraquer RI , Arnalich-Montiel F , Alio Del Barrio JL . Corneal graft failure: an update. Br J Ophthalmol 2021; 105(8): 1049–1058

[13]

Yan C , Zhao H , Pan Q , Xie X , Chen K , Zhang L . Novel treatments for bacterial keratitis: a review. Int J Pharm 2025; 681: 125793

[14]

Liu SH , Saldanha IJ , Abraham AG , Rittiphairoj T , Hauswirth S , Gregory D , Ifantides C , Li T . Topical corticosteroids for dry eye. Cochrane Database Syst Rev 2022; 10(10): CD015070

[15]

Khorrami-Nejad M , Hashemian H , Majdi A , Jadidi K , Aghamollaei H , Hadi A . Application of stem cell-derived exosomes in anterior segment eye diseases: a comprehensive update review. Ocul Surf 2025; 36: 209–219

[16]

Song Y , Liang F , Tian W , Rayhill E , Ye L , Tian X . Optimizing therapeutic outcomes: preconditioning strategies for MSC-derived extracellular vesicles. Front Pharmacol 2025; 16: 1509418

[17]

Zheng L , Gong H , Zhang J , Guo L , Zhai Z , Xia S , Hu Z , Chang J , Jiang Y , Huang X , Ge J , Zhang B , Yan M . Strategies to improve the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease. Front Bioeng Biotechnol 2023; 11: 1322514

[18]

Kalluri R , LeBleu VS . The biology, function, and biomedical applications of exosomes. Science 2020; 367(6478): eaau6977

[19]

Tian Y , Zhang T , Li J , Tao Y . Advances in development of exosomes for ophthalmic therapeutics. Adv Drug Deliv Rev 2023; 199: 114899

[20]

Cheng N , Luo Q , Yang Y , Shao N , Nie T , Deng X , Chen J , Zhang S , Huang Y , Hu K , Luo L , Xiao Z . Injectable pH responsive conductive hydrogel for intelligent delivery of metformin and exosomes to enhance cardiac repair after myocardial Ischemia-Reperfusion Injury. Adv Sci (Weinh) 2025; 12(24): 2410590

[21]

Wu M , Fletcher EL , Chinnery HR , Downie LE , Mueller SN . Redefining our vision: an updated guide to the ocular immune system. Nat Rev Immunol 2024; 24(12): 896–911

[22]

Feng H , Gong S , Liu J , Aghayants S , Liu Y , Wu M , Wu Y , Song J . Adipose-derived stem cell exosomes: mechanisms and therapeutic potentials in wound healing. Biomark Res 2025; 13(1): 88

[23]

Altug B , Soykan MN , Eyubova S , Eker Sariboyaci A , Dogan C , Ozalp O , Atalay E . Crosstalk among miR-29, α-SMA, and TGFβ1/β3 in melatonin-induced exosome (Mel-prExo) treated human limbal mesenchymal stem cells (hLMSCs): an insight into scarless healing of the cornea. Biofactors 2024; 50(6): 1287–1297

[24]

Desjardins P , Berthiaume R , Couture C , Le-Bel G , Roy V , Gros-Louis F , Moulin VJ , Proulx S , Chemtob S , Germain L , Guérin SL . Impact of exosomes released by different corneal cell types on the wound healing properties of human corneal epithelial cells. Int J Mol Sci 2022; 23(20): 12201

[25]

Verma N , Khare D , Poe AJ , Amador C , Ghiam S , Fealy A , Ebrahimi S , Shadrokh O , Song XY , Santiskulvong C , Mastali M , Parker S , Stotland A , Van Eyk JE , Ljubimov AV , Saghizadeh M . MicroRNA and protein cargos of human limbal epithelial cell-derived exosomes and their regulatory roles in limbal stromal cells of diabetic and non-diabetic corneas. Cells 2023; 12(21): 2524

[26]

Ryu Y , Hwang JS , Bo Noh K , Park SH , Seo JH , Shin YJ . Adipose mesenchymal stem cell-derived exosomes promote the regeneration of corneal endothelium through ameliorating senescence. Invest Ophthalmol Vis Sci 2023; 64(13): 29

[27]

Liang Y , Duan L , Lu J , Xia J . Engineering exosomes for targeted drug delivery. Theranostics 2021; 11(7): 3183–3195

[28]

Pegtel DM , Gould SJ . Exosomes. Annu Rev Biochem 2019; 88(1): 487–514

[29]

Lande K , Gupta J , Ranjan R , Kiran M , Torres Solis LF , Solís Herrera A , Aliev G , Karnati R . Exosomes: insights from retinoblastoma and other eye cancers. Int J Mol Sci 2020; 21(19): 7055

[30]

Wang Z , Yin R , Zhang L , Li S , Zhou Z , Sun M . Sulfafurazole dimers potentiate chemo-immunotherapy of low immunogenic breast cancer by preventing the PD-L1 exosomes secretion. Acta Pharm Sin B 2025; 15(5): 2673–2686

[31]

Yeat NY , Liu LH , Chang YH , Lai CP , Chen RH . Bro1 proteins determine tumor immune evasion and metastasis by controlling secretion or degradation of multivesicular bodies. Dev Cell 2025; 60(15): 2114–2130.e9

[32]

Sharma Y , Bhakuni S , Mathew CK , Vaishnav PK , Giri S , Mohanty S . Apoptosis linked gene-2 interacting protein X as a target to regulate the yield of small extracellular vesicles derived from tissue specific mesenchymal stem cells for translational applications. Int J Biol Macromol 2025; 318(Pt 2): 145092

[33]

Blanco-Agudín N , Ye S , Alcalde I , Corte-Torres MD , Galarreta D , Caro-Magdaleno M , Fernández-Vega I , Fernández-Vega Cueto L , Merayo-Lloves J , Quirós LM . Corneal stromal cells from patients with keratoconus exhibit alterations in the ESCRT-dependent machinery responsible for multivesicular body formation. Exp Eye Res 2025; 252: 110260

[34]

Trajkovic K , Hsu C , Chiantia S , Rajendran L , Wenzel D , Wieland F , Schwille P , Brügger B , Simons M . Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 2008; 319(5867): 1244–1247

[35]

Wei D , Zhan W , Gao Y , Huang L , Gong R , Wang W , Zhang R , Wu Y , Gao S , Kang T . RAB31 marks and controls an ESCRT-independent exosome pathway. Cell Res 2021; 31(2): 157–177

[36]

Wang Y , Yuan S , Zhou L , Yang K , Jin Z , Lin A , Yang C , Tian W . Cutting-edge progress in the acquisition, modification and therapeutic applications of exosomes for drug delivery. Int J Nanomedicine 2025; 20: 5059–5080

[37]

Arya SB , Collie SP , Parent CA . The ins-and-outs of exosome biogenesis, secretion, and internalization. Trends Cell Biol 2024; 34(2): 90–108

[38]

Bi Y , Qiao X , Liu Q , Song S , Zhu K , Qiu X , Zhang X , Jia C , Wang H , Yang Z , Zhang Y , Ji G . Systemic proteomics and miRNA profile analysis of exosomes derived from human pluripotent stem cells. Stem Cell Res Ther 2022; 13(1): 449

[39]

Kumar A , Yun H , Funderburgh ML , Du Y . Regenerative therapy for the cornea. Prog Retin Eye Res 2022; 87: 101011

[40]

Robbins BT , Montreuil KA , Kundu N , Kumar P , Agrahari V . Corneal treatment, repair, and regeneration: exosomes at rescue. Pharmaceutics 2024; 16(11): 1424

[41]

Leszczynska A , Kulkarni M , Ljubimov AV , Saghizadeh M . Exosomes from normal and diabetic human corneolimbal keratocytes differentially regulate migration, proliferation and marker expression of limbal epithelial cells. Sci Rep 2018; 8(1): 15173

[42]

Lozano V , Martín C , Blanco N , Alcalde I , Fernández-Vega Cueto L , Merayo-Lloves J , Quirós LM . Exosomes released by corneal stromal cells show molecular alterations in keratoconus patients and induce different cellular behavior. Biomedicines 2022; 10(10): 2348

[43]

Samaeekia R , Rabiee B , Putra I , Shen X , Park YJ , Hematti P , Eslani M , Djalilian AR . Effect of human corneal mesenchymal stromal cell-derived exosomes on corneal epithelial wound healing. Invest Ophthalmol Vis Sci 2018; 59(12): 5194–5200

[44]

Yu X , Wu X . Exosomal let-7b-5p derived from Aspergillus fumigatus-treated human corneal epithelial cells promotes M1 macrophage activation via targeting SOCS-1. Front Immunol 2025; 16: 1548802

[45]

Han KY , Tran JA , Chang JH , Azar DT , Zieske JD . Potential role of corneal epithelial cell-derived exosomes in corneal wound healing and neovascularization. Sci Rep 2017; 7(1): 40548

[46]

McKay TB , Hutcheon AEK , Zieske JD , Ciolino JB . Extracellular vesicles secreted by corneal epithelial cells promote myofibroblast differentiation. Cells 2020; 9(5): 1080

[47]

Hadvina R , Lotfy Khaled M , Akoto T , Zhi W , Karamichos D , Liu Y . Exosomes and their miRNA/protein profile in keratoconus-derived corneal stromal cells. Exp Eye Res 2023; 236: 109642

[48]

Hefley BS , McKay TB , Hutcheon AEK , Ciolino JB , Karamichos D . Corneal epithelial-stromal constructs to study differences associated with diabetes mellitus. Exp Eye Res 2024; 248: 110100

[49]

Ramos T , Parekh M , Kaye SB , Ahmad S . Epithelial cell-derived extracellular vesicles trigger the differentiation of two epithelial cell lines. Int J Mol Sci 2022; 23(3): 1718

[50]

Altshuler A , Amitai-Lange A , Tarazi N , Dey S , Strinkovsky L , Hadad-Porat S , Bhattacharya S , Nasser W , Imeri J , Ben-David G , Abboud-Jarrous G , Tiosano B , Berkowitz E , Karin N , Savir Y , Shalom-Feuerstein R . Discrete limbal epithelial stem cell populations mediate corneal homeostasis and wound healing. Cell Stem Cell 2021; 28(7): 1248–1261.e8

[51]

Jiang D , Li K , Sun Y , Zhang Z , Xie S , Yu X , Wang R , Feng Y , Zheng Q , Wen Y , Reinach PS , Du Y , Zhou M , Chen W . Spatiotemporal single-cell analysis elucidates the cellular and molecular dynamics of human cornea aging. Genome Med 2025; 17(1): 56

[52]

Ong HS , Riau AK , Yam GH , Yusoff NZBM , Han EJY , Goh TW , Lai RC , Lim SK , Mehta JS . Mesenchymal stem cell exosomes as immunomodulatory therapy for corneal scarring. Int J Mol Sci 2023; 24(8): 7456

[53]

Han KY , Chang JH , Azar DT . MMP14-containing exosomes cleave VEGFR1 and promote VEGFA-induced migration and proliferation of vascular endothelial cells. Invest Ophthalmol Vis Sci 2019; 60(6): 2321–2329

[54]

Han KY , Dugas-Ford J , Seiki M , Chang JH , Azar DT . Evidence for the involvement of MMP14 in MMP2 processing and recruitment in exosomes of corneal fibroblasts. Invest Ophthalmol Vis Sci 2015; 56(9): 5323–5329

[55]

Bogdan ED , Stuard WL , Titone R , Robertson DM . IGFBP-3 mediates metabolic homeostasis during hyperosmolar stress in the corneal epithelium. Invest Ophthalmol Vis Sci 2021; 62(7): 11

[56]

Mittal R , Patel S , Galor A . Alternative therapies for dry eye disease. Curr Opin Ophthalmol 2021; 32(4): 348–361

[57]

O’Neil EC , Henderson M , Massaro-Giordano M , Bunya VY . Advances in dry eye disease treatment. Curr Opin Ophthalmol 2019; 30(3): 166–178

[58]

Sullivan DA , Rocha EM , Aragona P , Clayton JA , Ding J , Golebiowski B , Hampel U , McDermott AM , Schaumberg DA , Srinivasan S , Versura P , Willcox MDP . TFOS DEWS II sex, gender, and hormones report. Ocul Surf 2017; 15(3): 284–333

[59]

Singh S , Maity M , Shanbhag S , Arunasri K , Basu S . Lid margin microbiome in Stevens–Johnson syndrome patients with lid margin keratinization and severe dry eye disease. Invest Ophthalmol Vis Sci 2024; 65(6): 28

[60]

Yu K , Bunya V , Maguire M , Asbell P , Ying GS; Dry Eye Assessment , Management Study Research Group . Systemic conditions associated with severity of dry eye signs and symptoms in the dry eye assessment and management study. Ophthalmology 2021; 128(10): 1384–1392

[61]

Kantor NB , Tovar A , Wang T , Galor A . How does ocular graft-versus-host disease fit under the dry eye umbrella? A review. Clin Exp Ophthalmol 2024; 52(2): 167–185

[62]

Periman LM , Perez VL , Saban DR , Lin MC , Neri P . The immunological basis of dry eye disease and current topical treatment options. J Ocul Pharmacol Ther 2020; 36(3): 137–146

[63]

Pflugfelder SC , de Paiva CS . The pathophysiology of dry eye disease: what we know and future directions for research. Ophthalmology 2017; 124(11S): S4–S13

[64]

Zhang Z , Liu C , Zhao L , Yao J . Systems biology of dry eye: unraveling molecular mechanisms through multi-omics integration. Ocul Surf 2025; 36: 25–40

[65]

Baral P , Kumaran SE , Stapleton F , Khong JJ , Carnt N , Wolffsohn JS , Pesudovs K . Understanding the quality-of-life impacts of ocular surface disease. Cont Lens Anterior Eye 2026; 49(1): 102482

[66]

Chen KY , Chan HC , Chan CM . How effective and safe are punctal plugs in treating dry eye disease? A systematic review and meta-analysis. Cont Lens Anterior Eye 2025; 48(5): 102438

[67]

Kawahara A . Treatment of dry eye disease (DED) in Asia: strategies for short tear film breakup time-type Ded. Pharmaceutics 2023; 15(11): 2591

[68]

Wang G , Zhu Y , Liu Y , Yang M , Zeng L . Mesenchymal stem cells-derived exosomal miR-223-3p alleviates ocular surface damage and inflammation by downregulating FBXW7 in dry eye models. Invest Ophthalmol Vis Sci 2024; 65(12): 1

[69]

Ma C , Li Y , Liu B , Deng J , Gao X , Zhang H , Zhang B , Zhou Q , Peng X , Zhang H . Exosomes derived from adipose mesenchymal stem cells promote corneal injury repair and inhibit the formation of scars by anti-apoptosis. Colloids Surf B Biointerfaces 2025; 247: 114454

[70]

Chan SM , Tsai C , Lee TP , Huang ZR , Huang WH , Lin CT . Therapeutic potential of umbilical cord MSC-derived exosomes in a severe dry eye rat model: enhancing corneal protection and modulating inflammation. Biomedicines 2025; 13(5): 1174

[71]

Tian Y , Zhang Y , Zhao J , Luan F , Wang Y , Lai F , Ouyang D , Tao Y . Combining MSC exosomes and cerium oxide nanocrystals for enhanced dry eye syndrome therapy. Pharmaceutics 2023; 15(9): 2301

[72]

Ma F , Feng J , Liu X , Tian Y , Wang WJ , Luan FX , Wang YJ , Yang WQ , Bai JY , Zhang YQ , Tao Y . A synergistic therapeutic nano-eyedrop for dry eye disease based on ascorbic acid-coupled exosomes. Nanoscale 2023; 15(4): 1890–1899

[73]

Liu X. Effect of Umscs derived exosomes on dry eye in patients with cGVHD. ClinicalTrials. gov. Updated February 10, 2022. NCT04213248

[74]

Gao Q. Safety and efficacy of pluripotent stem cell-derived mesenchymal stem cell exosome (PSC-MSc-Exo) eye drops treatment for dry eye diseases post refractive surgery and associated with blepharospasm. ClinicalTrials. gov. Published February 22, 2023. NCT05738629

[75]

Hassani AS. Limbal stem cell derived exosome (LSC-Exo) eye drop for treatment of dry eye (Exoiums). ClinicalTrials. gov. Updated May 1, 2025. NCT06543667

[76]

Farahani M , Patel R , Dwarakanathan S . Infectious corneal ulcers. Dis Mon 2017; 63(2): 33–37

[77]

Levine H , Sepulveda-Beltran PA , Amescua G . Rose bengal photodynamic antimicrobial therapy as potential adjuvant treatment for Serratia marcescens corneal ulcer. Am J Ophthalmol 2021; 231: e1–e2

[78]

Oh JY . Autoimmune keratitis after Atezolizumab treatment. N Engl J Med 2020; 383(15): 1468

[79]

NaPier E , Camacho M , McDevitt TF , Sweeney AR . Neurotrophic keratopathy: current challenges and future prospects. Ann Med 2022; 54(1): 666–673

[80]

Byanju R , Kandel RP , Poudyal B , Bhandari S , Ligal A , Pradhan S , Gautam M , Shrestha P , Sah RK , Gonzales JA , Porco TC , Whitcher JP , Srinivasan M , Upadhyay MP , Lietman TM , Keenan JD , O’Brien KS; Village-Integrated Eye Worker Trial Group . Risk factors for corneal ulcers: a population-based matched case-control study in Nepal. Br J Ophthalmol 2023; 107(12): 1771–1775

[81]

Hoffman JJ , Burton MJ , Leck A . Mycotic keratitis-a global threat from the filamentous fungi. J Fungi (Basel) 2021; 7(4): 273

[82]

Lu Y , Mo Y , Weng Y , Li X . Fungal keratitis caused by Neurospora: a case report. Front Med (Lausanne) 2024; 11: 1496010

[83]

Ortiz-Seller A , Hernández-Pons A , Pascual EV , Comín Pérez A , Dolz Gaitón R , Albert-Fort M . Severe cocaine-induced midline destructive lesions (Cimdl) leading to orbital apex syndrome and peripheral ulcerative keratitis. Ocul Immunol Inflamm 2022; 30(7-8): 1956–1960

[84]

Saucedo J , Lozano Feria FS , Ramírez A . Neurotrophic keratitis following vitrectomy surgery: a case report. Cureus 2025; 17(1): e77372

[85]

García-López C , Rodríguez-Calvo-de-Mora M , Borroni D , Sánchez-González JM , Romano V , Rocha-de-Lossada C . The role of matrix metalloproteinases in infectious corneal ulcers. Surv Ophthalmol 2023; 68(5): 929–939

[86]

Sosne G , Berger EA . Thymosin beta 4: a potential novel adjunct treatment for bacterial keratitis. Int Immunopharmacol 2023; 118: 109953

[87]

Xu X , Wei Y , Pang J , Wei Z , Wang L , Chen Q , Wang Z , Zhang Y , Chen K , Peng Y , Zhang Z , Liu J , Zhang Y , Jin ZB , Liang Q . Time-course transcriptomic analysis reveals the crucial roles of PANoptosis in fungal keratitis. Invest Ophthalmol Vis Sci 2023; 64(3): 6

[88]

Li M , Zhu L , Liu J , Huang H , Guo H , Wang L , Li L , Gu S , Tan J , Zhong J , Wang B , Mao Z , Fan Y , Liu C , Yuan J , Ouyang H . Loss of FOXC1 contributes to the corneal epithelial fate switch and pathogenesis. Signal Transduct Target Ther 2021; 6(1): 5

[89]

Santhiago MR , Morgado CR , Koo E , Iyer G , Srinivasan B , Berrospi R , Ghanem R . Corneal scar after ulcer in a young patient demanding visual restoration in a timely fashion treated with PTK + topo-guided PRK. J Cataract Refract Surg 2024; 50(12): 1293

[90]

Gao Q , Chu X , Yang J , Guo Y , Guo H , Qian S , Yang YW , Wang B . An antibiotic nanobomb constructed from pH-responsive chemical bonds in metal-phenolic network nanoparticles for biofilm eradication and corneal ulcer healing. Adv Sci (Weinh) 2024; 11(22): 2309086

[91]

Prajna NV , Lalitha P , Chandru S , Radhakrishnan N , Christy J , Karthikeyan A , Rajaraman R , Ramesh R , Amescua G , Mandlik K , Abdelrahman S , Varnado N , Kanchugantla M , Arnold B , Lietman TM , Rose-Nussbaumer JR . Steroids and cross-linking for ulcer treatment: the scut II randomized clinical trial. JAMA Ophthalmol 2025; 143(9): 723–730

[92]

Yoon CH , Choi HJ , Kim MK . Corneal xenotransplantation: where are we standing. Prog Retin Eye Res 2021; 80: 100876

[93]

Gupta A , El-Amin SF , Levy HJ , Sze-Tu R , Ibim SE , Maffulli N . Umbilical cord-derived Wharton’s jelly for regenerative medicine applications. J Orthop Surg Res 2020; 15(1): 49

[94]

Tu C , Gao X , Zheng H , Huang R , Yang F , Dong Y , Jing K , Groth T , Zhao M . Innovative injectable, self-healing, exosome cross-linked biomimetic hydrogel for cartilage regeneration. J Control Release 2025; 381: 113608

[95]

Gueudry J , Terkmane MN , Tétart F , Muraine M , Ingen-Housz-Oro S . Promising response to Wharton’s jelly eye drops in severe ocular involvement during acute phase of epidermal necrolysis and erythema multiforme major. J Eur Acad Dermatol Venereol 2025; 39(1): e75–e77

[96]

Cheng Y , Chen H , Gu S , Li W , Yu H , Zhang J , Zhang H , Lin J , Zhu H , Liu Y , Li W , Fu T , Zeng H , Wang T , Ling S . TLR3-overexpressing umbilical cord mesenchymal stromal cells suppress immune responses to attenuate high-risk corneal transplantation rejection. Stem Cell Res Ther 2025; 16(1): 370

[97]

Fan X , Zhang J , Dai Y , Shan K , Xu J . Blockage of P2X7R suppresses Th1/Th17-mediated immune responses and corneal allograft rejection via inhibiting NLRP3 inflammasome activation. Exp Eye Res 2021; 212: 108792

[98]

Laborante M , Micera A , Gaudenzi D , De Luca A , De Gregorio C , Cutrupi F , Esposito G , Balzamino BO , Laborante A , Coassin M , Di Zazzo A . VEGFR3 pathway in corneal transplantation. Acta Ophthalmol 2025; 103(4): e220–e230

[99]

Bhat M , Usmani SE , Azhie A , Woo M . Metabolic consequences of solid organ transplantation. Endocr Rev 2021; 42(2): 171–197

[100]

Wojciechowski D , Wiseman A . Long-term immunosuppression management: opportunities and uncertainties. Clin J Am Soc Nephrol 2021; 16(8): 1264–1271

[101]

Liu Y , Xu H , Yan N , Tang Z , Wang Q . Research progress of ophthalmic preparations of immunosuppressants. Drug Deliv 2023; 30(1): 2175925

[102]

Jia Z , Lv Y , Zhang W , Zhang X , Li F , Lu X , Zhao S . Mesenchymal stem cell derived exosomes-based immunological signature in a rat model of corneal allograft rejection therapy. Front Biosci (Landmark Ed) 2022; 27(3): 86

[103]

Wei C , Sun Y , Zeng F , Chen X , Ma L , Liu X , Qi X , Shi W , Gao H . Exosomal miR-181d-5p derived from rapamycin-conditioned MDSC alleviated allograft rejection by targeting KLF6. Adv Sci (Weinh) 2023; 10(34): 2304922

[104]

Yang J , Kang H , Liu Y , Lu S , Wu H , Zhang B , He Y , Zhou W . Harnessing tumor cell-derived exosomes for immune rejection management in corneal transplantation. Adv Sci (Weinh) 2025; 12(2): 2409207

[105]

Brown L , Leck AK , Gichangi M , Burton MJ , Denning DW . The global incidence and diagnosis of fungal keratitis. Lancet Infect Dis 2021; 21(3): e49–e57

[106]

Ung L , Bispo PJM , Shanbhag SS , Gilmore MS , Chodosh J . The persistent dilemma of microbial keratitis: global burden, diagnosis, and antimicrobial resistance. Surv Ophthalmol 2019; 64(3): 255–271

[107]

Stapleton F . The epidemiology of infectious keratitis. Ocul Surf 2023; 28: 351–363

[108]

Zhou H , Zhang H , Bi M , Zhang W . The role of PPAR in fungal keratitis. Front Immunol 2024; 15: 1454463

[109]

Gupta Y , Kishore A , Kumari P , Balakrishnan N , Lomi N , Gupta N , Vanathi M , Tandon R . Peripheral ulcerative keratitis. Surv Ophthalmol 2021; 66(6): 977–998

[110]

Gomes BF , Santhiago MR . Biology of peripheral ulcerative keratitis. Exp Eye Res 2021; 204: 108458

[111]

Bagraniya VK , Tripathi M , Ahmed NH , Sinha R , Sharma N , Kaur M , Titiyal JS , Agarwal T , Maharana P . Estimation of tear film concentration of oral ciprofloxacin in patients with bacterial keratitis. Eye Contact Lens 2025; 51(10): 470–474

[112]

Sharma N , Bagga B , Singhal D , Nagpal R , Kate A , Saluja G , Maharana PK . Fungal keratitis: a review of clinical presentations, treatment strategies and outcomes. Ocul Surf 2022; 24: 22–30

[113]

Xu J , Li P , Zhu X , Wang J , Cheng M , Song B . Development of reactive oxygen species-sensitive polyethylene glycol-modified voriconazole-loaded nanomicelles for treating fungal keratitis. Colloids Surf B Biointerfaces 2025; 256(Pt 1): 114988

[114]

Murray PJ , Wynn TA . Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011; 11(11): 723–737

[115]

An S , Anwar K , Ashraf M , Lee H , Jung R , Koganti R , Ghassemi M , Djalilian AR . Wound-healing effects of mesenchymal stromal cell secretome in the cornea and the role of exosomes. Pharmaceutics 2023; 15(5): 1486

[116]

Figueiredo GS , Stefanache T , Baylis OJ , Mudhar HS , Lako M , Figueiredo FC . Prospective consecutive case series of patients with neurotrophic keratopathy associated with unilateral total limbal stem cell deficiency caused by severe ocular surface burns. Ocul Surf 2025; 38: 195–202

[117]

Stepp MA , Zieske JD , Trinkaus-Randall V , Kyne BM , Pal-Ghosh S , Tadvalkar G , Pajoohesh-Ganji A . Wounding the cornea to learn how it heals. Exp Eye Res 2014; 121: 178–193

[118]

Sugioka K , Nishida T , Yunoki M , Mukai N , Murakami J , Kusaka S . Interactive effects of IL-1β and TGF-β on urokinase-type plasminogen activator and α-smooth muscle actin expression by corneal fibroblasts. Invest Ophthalmol Vis Sci 2025; 66(9): 56

[119]

Joyce NC . Proliferative capacity of the corneal endothelium. Prog Retin Eye Res 2003; 22(3): 359–389

[120]

Li H , Peng H , Ma B , Sun X , Zhang L , Chen B . DJ-1 promotes diabetic corneal epithelial wound healing by attenuating hyperglycemia-induced oxidative stress through inhibiting PTEN. Invest Ophthalmol Vis Sci 2025; 66(9): 20

[121]

Wang G , Li H , Long H , Gong X , Hu S , Gong C . Exosomes derived from mouse adipose-derived mesenchymal stem cells alleviate benzalkonium chloride-induced mouse dry eye model via inhibiting NLRP3 inflammasome. Ophthalmic Res 2022; 65(1): 40–51

[122]

Zhou J , Ding Y , Zhang Y , Zheng D , Yan L , Guo M , Mao Y , Yang L . Exosomes from bone marrow-derived mesenchymal stem cells facilitate corneal wound healing via regulating the p44/42 MAPK pathway. Graefes Arch Clin Exp Ophthalmol 2023; 261(3): 723–734

[123]

Lee S , Han J , Yang J , Lyu J , Park H , Bang J , Kim Y , Chang H , Park T . Exosomes from human iPSC-derived retinal organoids enhance corneal epithelial wound healing. Int J Mol Sci 2024; 25(16): 8925

[124]

Han X , Ju L , Sands M , Zhao Y , Irudayaraj J . Oxygenated exosome-based nanoeyedrop for mitigating hypoxia in corneal wound healing: impact on healing properties of human corneal epithelial cells. ACS Pharmacol Transl Sci 2025; 8(2): 602–612

[125]

Xu Y , Wei C , Ma L , Zhao L , Li D , Lin Y , Zhou Q , Xie L , Wang F . 3D mesenchymal stem cell exosome-functionalized hydrogels for corneal wound healing. J Control Release 2025; 380: 630–646

[126]

Yang GN , Roberts PK , Gardner-Russell J , Shah MH , Couper TA , Zhu Z , Pollock GA , Dusting GJ , Daniell M . From bench to clinic: Emerging therapies for corneal scarring. Pharmacol Ther 2023; 242: 108349

[127]

Fuest M , Jhanji V , Yam GH . Molecular and cellular mechanisms of corneal scarring and advances in therapy. Int J Mol Sci 2023; 24(9): 7777

[128]

Dandachli MH , Maier AB , Hofmann J , Dietrich-Ntoukas T . Comorbidities, clinical outcome and rate of herpes simplex positive PCR in patients with keratitis, corneal erosions and ulcers. J Ophthalmic Inflamm Infect 2025; 15(1): 59

[129]

Elbasiony E , Mittal SK , Pulimamidi VK , Luan T , Orr S , Dana R , Chauhan SK . Topical hepatocyte growth factor accelerates wound healing and inhibits scarring in experimental corneal injury. Cornea 2025; 44(10): 1296–1302

[130]

Kolenc A , Dimnik Ž , Marzidovšek M , Schollmayer P , Hawlina M , Maličev E , Lužnik Marzidovšek Z . Extracellular vesicle-derived bioactive molecules for corneal and ocular surface regeneration. J Clin Med 2025; 14(15): 5594

[131]

Ojanen ES , Turunen JA , Harju M . The incidence of serious anterior segment complications after selective laser trabeculoplasty. Acta Ophthalmol 2026; 104(S284): 106–113

[132]

Zhang H , Xu K , Wu JH , Qiao D , Tan XY , Rong S , Wang B , Leng XL , Wang K , Sun HL , Gao S , Chi W , Zhang JL . Antiferromagnetic dimanganese catalase mimics: targeting oxidative stress to mitigate corneal neovascularization post-alkali injury. J Am Chem Soc 2025; 147(34): 30967–30978

[133]

Sampaio LP , Hilgert GSL , Shiju TM , Santhiago MR , Wilson SE . Topical losartan and corticosteroid additively inhibit corneal stromal myofibroblast generation and scarring fibrosis after alkali burn injury. Transl Vis Sci Technol 2022; 11(7): 9

[134]

Shojaati G , Khandaker I , Funderburgh ML , Mann MM , Basu R , Stolz DB , Geary ML , Dos Santos A , Deng SX , Funderburgh JL . Mesenchymal stem cells reduce corneal fibrosis and inflammation via extracellular vesicle-mediated delivery of miRNA. Stem Cells Transl Med 2019; 8(11): 1192–1201

[135]

Tang Q , Lu B , He J , Chen X , Fu Q , Han H , Luo C , Yin H , Qin Z , Lyu D , Zhang L , Zhou M , Yao K . Exosomes-loaded thermosensitive hydrogels for corneal epithelium and stroma regeneration. Biomaterials 2022; 280: 121320

[136]

Bonnet C , González S , Deng SX . Ocular surface regeneration by limbal stem cells therapies: state of the art, challenges, and perspectives. Stem Cells Transl Med 2023; 12(11): 714–719

[137]

Le Q , Chauhan T , Yung M , Tseng CH , Deng SX . Outcomes of limbal stem cell transplant: a meta-analysis. JAMA Ophthalmol 2020; 138(6): 660–670

[138]

Reinprayoon U , Khramchantuk S , Kittimawikrom N , Ingrungruanglert P , Phodang S , Jaemthaworn T , Sriswasdi S , Israsena N . Single-cell analysis of heterogeneity and molecular changes in cultured corneal epithelial stem cells during serial passage. Stem Cells 2025; 43(10): sxaf041

[139]

Robertson SYT , Roberts JS , Deng SX . Regulation of limbal epithelial stem cells: importance of the niche. Int J Mol Sci 2021; 22(21): 11975

[140]

Zhang C , Mei H , Robertson SYT , Lee HJ , Deng SX , Zheng JJ . A small-molecule Wnt mimic improves human limbal stem cell ex vivo expansion. iScience 2020; 23(5): 101075

[141]

Bonnet C , Oh D , Mei H , Robertson S , Chang D , Bourges JL , Behar-Cohen F , Zheng JJ , Deng SX . Wnt6 plays a complex role in maintaining human limbal stem/progenitor cells. Sci Rep 2021; 11(1): 20948

[142]

Bonnet C , González S , Deng SX , Zheng JJ . Wnt activation as a potential therapeutic approach to treat partial limbal stem cell deficiency. Sci Rep 2023; 13(1): 15670

[143]

Niruthisard D , Bonnet C , Tanasugarn L , Le B , Deng SX . Autologous serum eye drops in the management of limbal stem cell deficiency associated with glaucoma surgery. Eye Contact Lens 2023; 49(1): 19–24

[144]

González S , Oh D , Baclagon ER , Zheng JJ , Deng SX . Wnt signaling is required for the maintenance of human limbal stem/progenitor cells in vitro. Invest Ophthalmol Vis Sci 2019; 60(1): 107–112

[145]

Gießl A , Khorolskaya J , Lochnit G , Timm T , Van Deun J , Zenkel M , Baur A , Kruse FE , Schlötzer-Schrehardt U . Effects of limbal niche cells-derived melanosomes and exosomes on human limbal epithelial stem/progenitor cells. Invest Ophthalmol Vis Sci 2024; 65(7): 1997

[146]

Di Girolamo N . Biologicals and biomaterials for corneal regeneration and vision restoration in limbal stem cell deficiency. Adv Mater 2024; 36(42): 2401763

[147]

Li C , An Y , Sun Y , Yang F , Xu Q , Wang Z . Adipose mesenchymal stem cell-derived exosomes promote wound healing through the Wnt/β-catenin signaling pathway in dermal fibroblasts. Stem Cell Rev Rep 2022; 18(6): 2059–2073

[148]

He L , Zhu C , Jia J , Hao XY , Yu XY , Liu XY , Shu MG . ADSC-Exos containing MALAT1 promotes wound healing by targeting miR-124 through activating Wnt/β-catenin pathway. Biosci Rep 2020; 40(5): BSR20192549

[149]

Elhusseiny AM , Soleimani M , Eleiwa TK , ElSheikh RH , Frank CR , Naderan M , Yazdanpanah G , Rosenblatt MI , Djalilian AR . Current and emerging therapies for limbal stem cell deficiency. Stem Cells Transl Med 2022; 11(3): 259–268

[150]

Duan M , Chen B , Yi X , Mahal A , Song L , Xu M , Obaidullah AJ , Yu S , Wang C . Doxorubicin delivery by pYEEIE peptide-functionalized rhodiola rosea-derived exosome-like nanovesicles for targeted melanoma therapy. Front Pharmacol 2025; 16: 1619998

[151]

Wang Z , Bi H , Li D , Zhang W , Wang C , Yang J , Shen X , Yan R , He F , Duan H . Bibliometric analysis of exosome research in spinal cord injury (2000–May 2024): trends, collaborations, and emerging insights. Drug Des Devel Ther 2025; 19: 6829–6848

[152]

Dave KM , Pinky PP , S Manickam D . Molecular engineering of extracellular vesicles for drug delivery: strategies, challenges, and perspectives. J Control Release 2025; 386: 114068

[153]

Chou CY , Chiang PC , Li CC , Chang JW , Lu PH , Hsu WF , Chang LC , Hsu JL , Wu MS , Wo AM . Improving the purity of extracellular vesicles by removal of lipoproteins from size exclusion chromatography- and ultracentrifugation-processed samples using glycosaminoglycan-functionalized magnetic beads. ACS Appl Mater Interfaces 2024; 16(34): 44386–44398

[154]

Valderrama OJ , Nischang I . Reincarnation of the analytical ultracentrifuge: emerging opportunities for nanomedicine. Anal Chem 2021; 93(48): 15805–15815

[155]

Ciftci E , Bozbeyoglu N , Gursel I , Korkusuz F , Bakan Misirlioglu F , Korkusuz P . Comparative analysis of magnetically activated cell sorting and ultracentrifugation methods for exosome isolation. PLoS One 2023; 18(2): e0282238

[156]

Bergqvist M , Lässer C , Crescitelli R , Park KS , Lötvall J . A non-centrifugation method to concentrate and purify extracellular vesicles using superabsorbent polymer followed by size exclusion chromatography. J Extracell Vesicles 2025; 14(1): e70037

[157]

Wei R , Zhao L , Kong G , Liu X , Zhu S , Zhang S , Min L . Combination of size-exclusion chromatography and ultracentrifugation improves the proteomic profiling of plasma-derived small extracellular vesicles. Biol Proced Online 2020; 22(1): 12

[158]

Sidhom K , Obi PO , Saleem A . A review of exosomal isolation methods: is size exclusion chromatography the best option. Int J Mol Sci 2020; 21(18): 6466

[159]

Lattmann E , Räss L , Tognetti M , Gómez JMM , Lapaire V , Bruderer R , Reiter L , Feng Y , Steinmetz LM , Levesque MP . Size-exclusion chromatography combined with DIA-MS enables deep proteome profiling of extracellular vesicles from melanoma plasma and serum. Cell Mol Life Sci 2024; 81(1): 90

[160]

Bai HH , Wang XF , Zhang BY , Liu W . A comparison of size exclusion chromatography-based tandem strategies for plasma exosome enrichment and proteomic analysis. Anal Methods 2023; 15(45): 6245–6251

[161]

Gurriaran-Rodriguez U , De Repentigny Y , Kothary R , Rudnicki MA . Isolation of small extracellular vesicles from regenerating muscle tissue using tangential flow filtration and size exclusion chromatography. Skelet Muscle 2024; 14(1): 22

[162]

Visan KS , Lobb RJ , Ham S , Lima LG , Palma C , Edna CPZ , Wu LY , Gowda H , Datta KK , Hartel G , Salomon C , Möller A . Comparative analysis of tangential flow filtration and ultracentrifugation, both combined with subsequent size exclusion chromatography, for the isolation of small extracellular vesicles. J Extracell Vesicles 2022; 11(9): 12266

[163]

Tangwattanachuleeporn M , Muanwien P , Teethaisong Y , Somparn P . Optimizing concentration of polyethelene glycol for exosome isolation from plasma for downstream application. Medicina (Kaunas) 2022; 58(11): 1600

[164]

Kee PE , Ng TC , Lan JC , Ng HS . Recent development of unconventional aqueous biphasic system: characteristics, mechanisms and applications. Crit Rev Biotechnol 2020; 40(4): 555–569

[165]

Wang C , Zhang D , Yang H , Shi L , Li L , Yu C , Wei J , Ding Q . A light-activated magnetic bead strategy utilized in spatio-temporal controllable exosomes isolation. Front Bioeng Biotechnol 2022; 10: 1006374

[166]

Chu Z , Song Y , Wu M , Zhu M , Meng B , Zhao Y , Zhai R , Dai X , Fang X . Programmable framework nucleic acid-modified nanomagnetic beads for efficient isolation of exosomes and exosomal proteomics analysis. Anal Chem 2024; 96(35): 14099–14107

[167]

Park M , Lee CH , Noh H , Kang G , Lee J , Bae JH , Moon H , Park J , Kong S , Baek MC , Park H . High-precision extracellular-vesicle isolation-analysis integrated platform for rapid cancer diagnosis directly from blood plasma. Biosens Bioelectron 2025; 267: 116863

[168]

Bu Y , Wang J , Ni S , Guo Y , Yobas L . Continuous-flow label-free size fractionation of extracellular vesicles through electrothermal fluid rolls and dielectrophoresis synergistically integrated in a microfluidic device. Lab Chip 2023; 23(10): 2421–2433

[169]

Krivitsky V , Krivitsky A , Mantella V , Ben-Yehuda Greenwald M , Sankar DS , Betschmann J , Bader J , Zoratto N , Schreier K , Feiss S , Walker D , Dengjel J , Werner S , Leroux JC . Ultrafast and controlled capturing, loading, and release of extracellular vesicles by a portable microstructured electrochemical fluidic device. Adv Mater 2023; 35(44): 2212000

[170]

Barnes B , Caws T , Thomas S , Shephard AP , Corteling R , Hole P , Bracewell DG . Investigating heparin affinity chromatography for extracellular vesicle purification and fractionation. J Chromatogr A 2022; 1670: 462987

[171]

Malvicini R , De Lazzari G , Tolomeo AM , Santa-Cruz D , Ullah M , Cirillo C , Grumati P , Pacienza N , Muraca M , Yannarelli G . Influence of the isolation method on characteristics and functional activity of mesenchymal stromal cell-derived extracellular vesicles. Cytotherapy 2024; 26(2): 157–170

[172]

Welsh JA , Goberdhan DCI , O'Driscoll L , Buzas EI , Blenkiron C , Bussolati B , Cai H , Di Vizio D , Driedonks TAP , Erdbrügger U , Falcon-Perez JM , Fu QL , Hill AF , Lenassi M , Lim SK , Mahoney MG , Mohanty S , Möller A , Nieuwland R , Ochiya T , Sahoo S , Torrecilhas AC , Zheng L , Zijlstra A , Abuelreich S , Bagabas R , Bergese P , Bridges EM , Brucale M , Burger D , Carney RP , Cocucci E , Crescitelli R , Hanser E , Harris AL , Haughey NJ , Hendrix A , Ivanov AR , Jovanovic-Talisman T , Kruh-Garcia NA , Ku'ulei-Lyn Faustino V , Kyburz D , Lässer C , Lennon KM , Lötvall J , Maddox AL , Martens-Uzunova ES , Mizenko RR , Newman LA , Ridolfi A , Rohde E , Rojalin T , Rowland A , Saftics A , Sandau US , Saugstad JA , Shekari F , Swift S , Ter-Ovanesyan D , Tosar JP , Useckaite Z , Valle F , Varga Z , van der Pol E , van Herwijnen MJC , Wauben MHM , Wehman AM , Williams S , Zendrini A , Zimmerman AJ; MISEV Consortium; Théry C , Witwer KW . Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J Extracell Vesicles 2024; 13(2): e12404

[173]

Lai JJ , Chau ZL , Chen SY , Hill JJ , Korpany KV , Liang NW , Lin LH , Lin YH , Liu JK , Liu YC , Lunde R , Shen WT . Exosome processing and characterization approaches for research and technology development. Adv Sci (Weinh) 2022; 9(15): 2103222

[174]

Sharma P , Dhamija RK , Nag TC , Roy A , Inampudi KK . Different biofluids, small extracellular vesicles or exosomes: structural analysis in atherosclerotic cardiovascular disease using electron microscopy techniques. Microsc Microanal 2023; 29(3): 1168–1177

[175]

Zhao Q , Zhang Y , Xiao L , Lu H , Ma Y , Liu Q , Wang X . Surface engineering of titania nanotubes incorporated with double-layered extracellular vesicles to modulate inflammation and osteogenesis. Regen Biomater 2021; 8(3): rbab010

[176]

Li H , Hu Y , Zeng M , Yang J , Fan X , Wang Y , Xie J . Exosomes from human urine-derived stem cells encapsulated into PLGA nanoparticles for therapy in mice with particulate polyethylene-induced osteolysis. Front Med (Lausanne) 2021; 8: 781449

[177]

Nishimura H , Hashii N , Yamamoto T , Sun Y , Miura T , Sato Y , Ishii-Watabe A . Usefulness of size-exclusion chromatography-multi-angle light scattering to assess particle composition and protein impurities for quality control of therapeutic exosome preparations. Pharmaceutics 2024; 16(12): 1526

[178]

Resch U , Hackl H , Pereyra D , Santol J , Brunnthaler L , Probst J , Jankoschek AS , Aiad M , Nolte H , Krueger M , Starlinger P , Assinger A . SILAC-based characterization of plasma-derived extracellular vesicles in patients undergoing partial hepatectomy. Int J Mol Sci 2024; 25(19): 10685

[179]

Xu CX , Huang W , Shi XJ , Du Y , Liang JQ , Fang X , Chen HY , Cheng Y . Dysregulation of serum exosomal lipid metabolism in schizophrenia: a biomarker perspective. Mol Neurobiol 2025; 62(3): 3556–3567

[180]

Shkryl Y , Tsydeneshieva Z , Menchinskaya E , Rusapetova T , Grishchenko O , Mironova A , Bulgakov D , Gorpenchenko T , Kazarin V , Tchernoded G , Bulgakov V , Aminin D , Yugay Y . Exosome-like nanoparticles, high in trans-δ-viniferin derivatives, produced from grape cell cultures: preparation, characterization, and anticancer properties. Biomedicines 2024; 12(9): 2142

[181]

Yang H , Wu P , Li B , Huang X , Shi Q , Qiao L , Liu B , Chen X , Fang X . Diagnosis and biomarker screening of endometrial cancer enabled by a versatile exosome metabolic fingerprint platform. Anal Chem 2024; 96(44): 17679–17688

[182]

Qi Y , Xu R , Song C , Hao M , Gao Y , Xin M , Liu Q , Chen H , Wu X , Sun R , Zhang Y , He D , Dai Y , Kong C , Ning S , Guo Q , Zhang G , Wang P . A comprehensive database of exosome molecular biomarkers and disease-gene associations. Sci Data 2024; 11(1): 210

[183]

Buono L , Scalabrin S , De Iuliis M , Tanzi A , Grange C , Tapparo M , Nuzzi R , Bussolati B . Mesenchymal stem cell-derived extracellular vesicles protect human corneal endothelial cells from endoplasmic reticulum stress-mediated apoptosis. Int J Mol Sci 2021; 22(9): 4930

[184]

Lee SH , Koh A , Lee SJ , Lee H , Kim KW . M2a macrophage-dominant microenvironment in inflammation attenuation and wound healing of human corneal endothelial cells. Invest Ophthalmol Vis Sci 2025; 66(6): 35

[185]

Lee SJ , Lee SH , Koh A , Kim KW . EGF-conditioned M1 macrophages convey reduced inflammation into corneal endothelial cells through exosomes. Heliyon 2024; 10(5): e26800

[186]

Tati V , Muthukumar V S , Shukla S . Mesenchymal vs. epithelial extracellular vesicles in corneal epithelial repair, apoptosis, and immunomodulation: an in vitro study. Exp Eye Res 2024; 247: 110027

[187]

Yeung V , Boychev N , Kanu LN , Ng V , Ross AE , Hutcheon AEK , Ciolino JB . Proteomic characterization of corneal epithelial and stromal cell-derived extracellular vesicles. Int J Mol Sci 2024; 25(19): 10338

[188]

Liu C , Cheng C , Cheng K , Gao AS , Li Q , Atala A , Zhang Y . Precision exosome engineering for enhanced wound healing and scar revision. J Transl Med 2025; 23(1): 578

[189]

Chen H , Li N , Cai Y , Ma C , Ye Y , Shi X , Guo J , Han Z , Liu Y , Wei X . Exosomes in neurodegenerative diseases: therapeutic potential and modification methods. Neural Regen Res 2026; 21(2): 478–490

[190]

Mondal J , Pillarisetti S , Junnuthula V , Saha M , Hwang SR , Park IK , Lee YK . Hybrid exosomes, exosome-like nanovesicles and engineered exosomes for therapeutic applications. J Control Release 2023; 353: 1127–1149

[191]

Chen M , Lu Y , Liu Y , Liu Q , Deng S , Liu Y , Cui X , Liang J , Zhang X , Fan Y , Wang Q . Injectable microgels with hybrid exosomes of chondrocyte-targeted FGF18 gene-editing and self-renewable lubrication for osteoarthritis therapy. Adv Mater 2024; 36(16): 2312559

[192]

Fang C , Huang L , Gu J , Song T . Exosomal irisin from FNDC5-engineered BMSCs improves ischemic stroke via inhibiting YAP/EGR1/ACSL4-mediated ferroptosis. Exp Neurol 2025; 387: 115172

[193]

Lee YH , Huang CY . Engineered perfluorochemical cancer-derived exosomes loaded with indocyanine green and camptothecin provide targeted photochemotherapy for effective cancer treatment. Int J Nanomedicine 2025; 20: 327–342

[194]

Zhai Y , Zhang Y , Xu K , Wang T , Zhiqun Bian , Qu L , Wu F , Hu Z , Chang X , Li H , Zhang C , Li C , Shi C . Cordycepin ameliorates spaceflight-induced osteoporosis by preventing BMSCs oxidative stress and senescence via interacting with PI3K p110α and regulating PI3K/Akt/FOXO3 signalling. Free Radic Biol Med 2025; 228: 108–125

[195]

Xu X , Shen Y , Wu J , Hong F , Xia H , Chen X , Lin G , Liu L , Xu RA . Methacrylated sericin/methacrylated hyaluronic acid composite microneedles with exosomes for diabetic wound healing. Int J Biol Macromol 2025; 318(Pt 1): 144957

[196]

Kučuk N , Primožič M , Knez Ž , Leitgeb M . Exosomes engineering and their roles as therapy delivery tools, therapeutic targets, and biomarkers. Int J Mol Sci 2021; 22(17): 9543

[197]

Afzal M , Hameed H , Paiva-Santos AC , Saleem M , Hameed A , Ahmad SM . Bioengineered exosomes: cellular membrane-camouflaged biomimetic nanocarriers for Parkinson’s disease management. Eur J Pharmacol 2025; 987: 177199

[198]

Wang Y , Sun L , Dong Z , Zhang T , Wang L , Cao Y , Xu H , Liu C , Chen B . Targeted inhibition of ferroptosis in bone marrow mesenchymal stem cells by engineered exosomes alleviates bone loss in smoking-related osteoporosis. Mater Today Bio 2025; 31: 101501

[199]

Zhang L , Kao G , Zhao Y , Zhang Z , Kim HS , Shi X , Cheng Q , Hou T , Lenz HJ , Zhang Y . Genetically reprogrammed exosomes for immunotherapy of acute myeloid leukemia. Mol Ther 2025; 33(3): 1091–1104

[200]

Wang CK , Tsai TH , Lee CH . Regulation of exosomes as biologic medicines: regulatory challenges faced in exosome development and manufacturing processes. Clin Transl Sci 2024; 17(8): e13904

[201]

Cheng K , Kalluri R . Guidelines for clinical translation and commercialization of extracellular vesicles and exosomes based therapeutics. Extracell Vesicle 2023; 2: 100029

[202]

Verma N , Arora S . Navigating the global regulatory landscape for exosome-based therapeutics: challenges, strategies, and future directions. Pharmaceutics 2025; 17(8): 990

[203]

Bao Q , Zhang X , Hao Z , Li Q , Wu F , Wang K , Li Y , Li W , Gao H . Advances in polysaccharide-based microneedle systems for the treatment of ocular diseases. Nano-Micro Lett 2024; 16(1): 268

[204]

Wang C , Pang Y . Nano-based eye drop: topical and noninvasive therapy for ocular diseases. Adv Drug Deliv Rev 2023; 194: 114721

[205]

Kato JM , Ballalai PL , de Lima PP , Santo RM . Efficacy and safety of topical 0.5% 5-fluorouracil as primary treatment of ocular surface squamous neoplasia. Can J Ophthalmol 2024; 59(5): e510–e514

[206]

Lee S , Jung MY , Park CY . Development of a conjunctival contact-type drug delivery device for latanoprost using hyaluronic acid. Drug Deliv 2025; 32(1): 2459775

[207]

Gomes Souza L , Antonio Sousa-Junior A , Alves Santana Cintra B , Vieira Dos Anjos JL , Leite Nascimento T , Palmerston Mendes L , de Souza Vieira M , do Nascimento Ducas R , Campos Valadares M , Antônio Mendanha S , Martins Lima E . Pre-clinical safety of topically administered sunitinib-loaded lipid and polymeric nanocarriers targeting corneal neovascularization. Int J Pharm 2023; 635: 122682

[208]

Oz Y , Zheng Y , Kumar P , Kumar LK , Roy A , Qi I , Liu ZJ , Singh PK , Annabi N . Mucoadhesive tannic acid-cross-linked nanogels for reactive oxygen species scavenging and enhanced ocular therapeutic delivery. ACS Nano 2025; 19(30): 27173–27191

[209]

Tang B , Wang Q , Zhang G , Zhang A , Zhu L , Zhao R , Gu H , Meng J , Zhang J , Fang G . OCTN2- and ATB0,+-targeted nanoemulsions for improving ocular drug delivery. J Nanobiotechnology 2024; 22(1): 130

[210]

Kompella UB , Hartman RR , Patil MA . Extraocular, periocular, and intraocular routes for sustained drug delivery for glaucoma. Prog Retin Eye Res 2021; 82: 100901

[211]

Friling E , Bro T , Lundström M , Montan P . Endophthalmitis after cataract surgery and effect of different intracameral antibiotic regimes in Sweden 2011-2017: national registry study. J Cataract Refract Surg 2024; 50(8): 828–835

[212]

Vasudevan A , Jozić A , Curtis AG , Bodi E , Ryals RC , Sahay G . Lipid nanoparticle-mediated intracameral mRNA delivery facilitates gene expression and editing in the anterior chamber of the eye. J Control Release 2025; 379: 1022–1028

[213]

Kim J , Han LS , Robinson L , Young-Zvandasara T . Randomised controlled trial: influence of subconjunctival anaesthesia duration on pain perception during intravitreal injections. Clin Exp Ophthalmol 2025; 53(8): 918–924

[214]

Roddy GW , Kohli D , Niknam P , Omer ME , Chowdhury UR , Anderson KJ , Pacheco Marrero JM , Rinkoski TA , Fautsch MP . Subconjunctival administration of an adeno-associated virus expressing stanniocalcin-1 provides sustained intraocular pressure reduction in mice. Ophthalmol Sci 2025; 5(1): 100590

[215]

Couret C , Quintart PA , Poinas A , Vibet MA , Le Lez ML , Labalette P , Bodaghi B , Labetoulle M , Rougier MB , Angioi K , Chiquet C , Titah C , Kodjikian L , Baillif S , Creuzot-Garcher C , Errera MH , Weber M . Comparison of subconjunctival TRIamcinolone acetonide injection and intravitreal dexamethasone (OZurdex) injection for uveitic and postoperative macular oedema: the TRIOZ study. Br J Ophthalmol 2025; 109(2): 215–222

[216]

Yu F , Zhao X , Wang Q , Fang PH , Liu L , Du X , Li W , He D , Zhang T , Bai Y , Liu L , Li S , Yuan J . Engineered mesenchymal stromal cell exosomes-loaded microneedles improve corneal healing after chemical injury. ACS Nano 2024; 18(31): 20065–20082

[217]

Adak S , Jadhav VS , Khatri DK . Emerging innovations in ophthalmic drug delivery for diabetic retinopathy: a translational perspective. Drug Deliv Transl Res 2026; 16: 1064–1095

[218]

VandenBerg MA , Zaman RU , Plavchak CL , Smith WC , Nejad HB , Beringhs AO , Wang Y , Xu X . Impact of polymer source variations on hydrogel structure and product performance in dexamethasone-loaded ophthalmic inserts. Int J Pharm 2025; 682: 125959

[219]

Zhang M , Zhang SY , Zhang H , Liu Y , Dong Y , Han D , Chang L , Yang N , Tian J , Wang Y , Ye Q . Photocontrolled bionic micro-nano hydrogel system used novel functional strategy for cell delivery and large-scale corneal repair. Adv Healthc Mater 2025; 14(9): 2403444

[220]

Yang M , Chen X , Chen Z , Zhao N , Zeng Z , Huang X , Li Z , Li J , Zhao G , Deng M , Zou Z , Pan H , Chen A , Chen T , Wu Y , Fu X , Saiding Q , Kong N , Tao W , Zhou X , Huang J . Thermoresponsive antioxidant metal-free carbon nanodot hydrogel: an effective therapeutic approach for ocular surface disease. Sci Adv 2025; 11(30): eadt8775

[221]

Al Yabhouni SA , Mozumder MS , Hassan N , Mourad AI , Issa Md TMA . Nanocarrier-based, ocular drug delivery: challenges, prospects, and the therapeutic landscape in the United Arab Emirates. Int J Pharm 2024; 667(Pt B): 124899

[222]

Kurl S , Mittal N , Kaur G . Advancing ocular therapeutics: the role of alginate hydrogels in overcoming drug delivery barriers—a review. Int J Biol Macromol 2025; 321(Pt 2): 146319

[223]

Tang H , Li X , Li C , Shen W , Jin L , Zhou Y , Jiao W , Zhang L , Cheng F . Sequential delivery of anti-inflammatory and anti-scar drugs by Rg3 liposome-embedded thiolated chitosan hydrogel eye drops for corneal alkali burn. Carbohydr Polym 2025; 361: 123626

[224]

Abdelghany TM , Vo N , Vukajlovic D , Smith E , Wong JZ , Jackson E , Hilkens CMU , Lau WM , Ng KW , Novakovic K . Engineering and in vitro evaluation of semi-dissolving, hydrogel-forming polymeric microneedles for sustained-release drug delivery. Int J Pharm 2025; 682: 125932

[225]

Xiao X , Zhou Y , Lin S , Chen H , Dai R . Evaluation of calcium alginate hydrogel for suprachoroidal buckling in a rabbit model-a pilot study on efficacy and biocompatibility. Front Med (Lausanne) 2025; 12: 1632889

[226]

Ni X , Zhao Y , Zhu J , Liu Y , Zhang Z , Zhang H , Liu Q , Jiang Q , Gao S , Yan B . Hyaluronic acid methacryloyl-based co-delivery system for aflibercept and miR-21-3p antagomir: a dual-therapeutic approach for diabetic retinopathy. J Control Release 2025; 386: 114077

[227]

Zhao L , Shi Z , Zhang X , Wang J , Yang S , Wang F , Li T , Zhou Q , Wang T , Shi W . Artificial cornea substitute based on hydrogel skeletons with natural stromal hierarchical structure and extracellular matrix for sutureless transplantation. Adv Sci (Weinh) 2025; 12(19): 2411540

[228]

Wang T , Cao W , Wang X , Dong M , Yu L , Feng Y , Yang N , Song H . Composite synthetic protein hydrogel for inhibition of corneal fibrosis and treatment of corneal wounds. Int J Biol Macromol 2025; 307(Pt 2): 142013

[229]

Bian Q , Li H . Fully reshapeable and recyclable protein hydrogels. Adv Mater 2025; 37(42): e09812

[230]

Li R , Qi Q , Jiang X , Gao Z , Xie X , Zhao Y , Cheng X , Wang C , Hou G , Li C . Exosome microsphere/nano silver loaded injectable antibacterial hydrogel augments anti-infection and healing for scald wound. Front Microbiol 2025; 16: 1550276

[231]

Zhao X , Shi Y , Sun Z , Duan W , Chang L , Xu B , Lai K , Zhang J , Tian B , Tao W , Mi Z , Zhang M , Yang W , Luo Z , Ye Z . Injectable hydrogel loaded with exosomes from hypoxic umbilical cord-derived mesenchymal stem cells alleviates intervertebral disc degeneration by reversing nucleus pulposus cell senescence. Regen Biomater 2025; 12: rbaf039

[232]

Yu H , Zhang J , Yang L , Tian Y , Milne C , Jin P , Li Q , Song R , Wang W . MSC-derived exosomes injectable hyaluronic acid hydrogel for enhanced chronic wound healing. J Control Release 2025; 385: 113985

[233]

Sun D , Yu H , Shen H , Wang Y , Su T , Guo H , Xing X , Wang W , Wei L , Gao W , Yao Y , Xiu B , Wang J , Zhang X , Guo Y . Sodium alginate hydrogel platelet rich plasma exosome loaded for synergistic hemostasis. Int J Biol Macromol 2025; 311(Pt 1): 143447

[234]

Choi J , Shim S , Shin J , Lee A , Strang J , Braun T , Naef R , Jung H . Suprachoroidal space-inducing hydrogel-forming microneedles (SI-HFMN): an innovative platform for drug delivery to the posterior segment of the eye. Bioact Mater 2025; 50: 47–60

[235]

Zhu Z , Luo Y , Xiao P , Xie Y , Zhang J , Huang K , Wu X , Lu K , Zhang Y , Tan J , Chen H , Huang W , Lei Y , Liao J . Carrier rocket-inspired hydrogel microspheres targeting subchondral bone osteoclast activity alleviate osteoarthritic pain and cartilage degeneration. J Nanobiotechnology 2025; 23(1): 551

[236]

Lei M , Ji Y , Zhang S , Hou B , Lu Y , Sun J , Liu C , Qu X . Engineering a functionality-integrated artificial cornea stromal Substitute: Janus bio-adhesive implant with a collagen-based multi-scale biomimetic skeleton. Bioact Mater 2025; 51: 740–757

[237]

Wang W , Cheng Z , Yu M , Liu K , Duan H , Zhang Y , Huang X , Li M , Li C , Hu Y , Luo Z , Liu M . Injectable ECM-mimetic dynamic hydrogels abolish ferroptosis-induced post-discectomy herniation through delivering nucleus pulposus progenitor cell-derived exosomes. Nat Commun 2025; 16(1): 3131

[238]

Sun X , Song W , Teng L , Huang Y , Liu J , Peng Y , Lu X , Yuan J , Zhao X , Zhao Q , Xu Y , Shen J , Peng X , Ren L . MiRNA 24-3p-rich exosomes functionalized DEGMA-modified hyaluronic acid hydrogels for corneal epithelial healing. Bioact Mater 2023; 25: 640–656

[239]

Brezgin S , Parodi A , Kostyusheva A , Ponomareva N , Lukashev A , Sokolova D , Pokrovsky VS , Slatinskaya O , Maksimov G , Zamyatnin AA Jr , Chulanov V , Kostyushev D . Technological aspects of manufacturing and analytical control of biological nanoparticles. Biotechnol Adv 2023; 64: 108122

[240]

Gutiérrez-Sandoval R , Gutiérrez-Castro F , Muñoz-Godoy N , Rivadeneira I , Sobarzo A , Alarcón L , Dorado W , Lagos A , Montenegro D , Muñoz I , Aguilera R , Iturra J , Krakowiak F , Peña-Vargas C , Toledo A . The design of a multistage monitoring protocol for dendritic cell-derived exosome (DEX) immunotherapy: a conceptual framework for molecular quality control and immune profiling. Int J Mol Sci 2025; 26(12): 5444

[241]

Ma CY , Zhai Y , Li CT , Liu J , Xu X , Chen H , Tse HF , Lian Q . Translating mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: promises, problems and prospects. Med Res Rev 2024; 44(3): 919–938

[242]

Wei R , Wang Y , Feng Z , Liu R , Liu C , Hu X , Liu Y , Kong B , Zhou X , Li M . Self-healing adhesive oxidized guar gum hydrogel loaded with mesenchymal stem cell exosomes for corneal wound healing. J Nanobiotechnology 2025; 23(1): 321

[243]

Bhujel B , Oh SH , Kim CM , Yoon YJ , Kim YJ , Chung HS , Ye EA , Lee H , Kim JY . Mesenchymal stem cells and exosomes: a novel therapeutic approach for corneal diseases. Int J Mol Sci 2023; 24(13): 10917

[244]

Chen L , Gu C , Yang Y , He T , Zhang Q . Exosomal miR-146a derived from human umbilical cord mesenchymal stem cells alleviates inflammation and apoptosis in dry eye disease by targeting SQSTM1. Exp Eye Res 2025; 258: 110490

[245]

Chen L , Li S , Fu Y . MicroRNAs in corneal diseases: emerging roles as biomarkers, regulators, and therapeutics. Ocul Surf 2025; 38: 14–30

[246]

Khaled ML , Bykhovskaya Y , Yablonski SER , Li H , Drewry MD , Aboobakar IF , Estes A , Gao XR , Stamer WD , Xu H , Allingham RR , Hauser MA , Rabinowitz YS , Liu Y . Differential expression of coding and long noncoding RNAs in keratoconus-affected corneas. Invest Ophthalmol Vis Sci 2018; 59(7): 2717–2728

[247]

López-López M , Regueiro U , Bravo SB , Chantada-Vázquez MDP , Pena C , Díez-Feijoo E , Hervella P , Lema I . Shotgun proteomics for the identification and profiling of the tear proteome of keratoconus patients. Invest Ophthalmol Vis Sci 2022; 63(5): 12

[248]

Li SY. Exploratory clinical study on the safety and efficacy of human umbilical cord mesenchymal stem cell-derived exosome eye drops for the treatment of dry eye disease associated with Sjögren’s syndrome. Chinese Clinical Trial Registry. Published March 31, 2025. ChiCTR2500099859

[249]

Li J , Wang J , Chen Z . Emerging role of exosomes in cancer therapy: progress and challenges. Mol Cancer 2025; 24(1): 13

[250]

Song J , Song B , Yuan L , Yang G . Multiplexed strategies toward clinical translation of extracellular vesicles. Theranostics 2022; 12(15): 6740–6761

[251]

Ng KS , Smith JA , McAteer MP , Mead BE , Ware J , Jackson FO , Carter A , Ferreira L , Bure K , Rowley JA , Reeve B , Brindley DA , Karp JM . Bioprocess decision support tool for scalable manufacture of extracellular vesicles. Biotechnol Bioeng 2019; 116(2): 307–319

[252]

Liu F , Vermesh O , Mani V , Ge TJ , Madsen SJ , Sabour A , Hsu EC , Gowrishankar G , Kanada M , Jokerst JV , Sierra RG , Chang E , Lau K , Sridhar K , Bermudez A , Pitteri SJ , Stoyanova T , Sinclair R , Nair VS , Gambhir SS , Demirci U . The exosome total isolation chip. ACS Nano 2017; 11(11): 10712–10723

[253]

Jung J , Lenzini S , Rehmann M , Zakhem E , Dugan A , Budiman M . Development of a high yield/high purity exosome downstream process that retains critical quality attributes. Cytotherapy 2025; 27(Suppl 5): S80–S81

[254]

Wani TU , Mohi-Ud-Din R , Mir RH , Itoo AM , Mir KB , Fazli AA , Pottoo FH . Exosomes harnessed as nanocarriers for cancer therapy—current status and potential for future clinical applications. Curr Mol Med 2021; 21(9): 707–723

[255]

Jiang S , Li H , Zhang L , Mu W , Zhang Y , Chen T , Wu J , Tang H , Zheng S , Liu Y , Wu Y , Luo X , Xie Y , Ren J . Generic Diagramming Platform (GDP): a comprehensive database of high-quality biomedical graphics. Nucleic Acids Res 2025; 53(D1): D1670–D1676

RIGHTS & PERMISSIONS

Higher Education Press

PDF (3984KB)

446

Accesses

0

Citation

Detail

Sections
Recommended

/