{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:12:08Z","timestamp":1792789928742,"version":"4.5.0"},"reference-count":120,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82501306"],"award-info":[{"award-number":["82501306"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["82602148"],"award-info":[{"award-number":["82602148"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"award":["82501306"],"award-info":[{"award-number":["82501306"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82602148"],"award-info":[{"award-number":["82602148"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Nanjing Health Technology Development Project for Young Talents","award":["QNX25114"],"award-info":[{"award-number":["QNX25114"]}]},{"name":"Nanjing Health Technology Development Project for Young Talents","award":["QNX25113"],"award-info":[{"award-number":["QNX25113"]}]},{"name":"General Project of the Basic Science Foundation (Natural science) of Jiangsu Province Ordinary Higher Education Institutions","award":["24KJB320008"],"award-info":[{"award-number":["24KJB320008"]}]},{"name":"Nanjing Medical University Science and Technology Development Fund","award":["NMUB20250128"],"award-info":[{"award-number":["NMUB20250128"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Ocular diseases remain a major global health challenge with substantial unmet therapeutic needs. Small nucleic acid therapeutics offer a precise strategy to regulate disease-related mRNAs or noncoding RNAs through base pairing, thereby modulating protein expression at the RNA level. Major modalities include antisense oligonucleotides, small interfering RNAs, microRNA-based therapeutics, small activating RNAs, and nucleic acid aptamers, which act through RNA degradation, RNA interference, splicing modulation, microRNA regulation, transcriptional activation, or structure-dependent target binding. These properties make them attractive for ocular diseases involving genetic defects, pathological angiogenesis, inflammation, fibrosis, or neurodegeneration. However, their clinical translation in ophthalmology remains limited by poor molecular stability, insufficient tissue retention, immune activation, off-target effects, and inefficient delivery to target ocular tissues. Rational oligonucleotide design, appropriate local administration routes, and optimized delivery platforms are therefore essential for improving stability, tissue penetration, cellular uptake, and therapeutic durability. This review summarizes the major classes, mechanisms, chemical modification strategies, ocular delivery systems, and therapeutic applications of small nucleic acid drugs in ophthalmology. We also discuss lessons from clinical successes and failures and propose future directions for safe, durable, and individualized ocular therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091189","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:03:47Z","timestamp":1789977827000},"page":"1189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Small Nucleic Acid Therapeutics for Ocular Diseases: Progress, Challenges, and Future Perspectives"],"prefix":"10.3390","volume":"18","author":[{"given":"Qi","family":"Guo","sequence":"first","affiliation":[{"name":"Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, China"},{"name":"The Fourth School of Clinical Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lushu","family":"Chen","sequence":"additional","affiliation":[{"name":"Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, China"},{"name":"The Fourth School of Clinical Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, China"},{"name":"The Fourth School of Clinical Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, China"},{"name":"The Fourth School of Clinical Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinsong","family":"Xue","sequence":"additional","affiliation":[{"name":"Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, China"},{"name":"The Fourth School of Clinical Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing 210029, China"},{"name":"The Fourth School of Clinical Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2019). World Report on Vision, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1136\/bjophthalmol-2011-300581","article-title":"Surgical outcome and risk stratification for primary retinal detachment repair: Results from the Scottish Retinal Detachment study","volume":"96","author":"Mitry","year":"2012","journal-title":"Br. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"109162","DOI":"10.1016\/j.exer.2022.109162","article-title":"Quantitative pharmacokinetic analyses of anterior and posterior elimination routes of intravitreal anti-VEGF macromolecules using published human and rabbit data","volume":"222","author":"Lamminsalo","year":"2022","journal-title":"Exp. Eye Res."},{"key":"ref_4","first-page":"5397","article-title":"Intravitreal anti-VEGF injections for treating wet age-related macular degeneration: A systematic review and meta-analysis","volume":"9","author":"Ba","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S78","DOI":"10.1016\/j.ophtha.2016.04.056","article-title":"Anti-Vascular Endothelial Growth Factor Agents in the Treatment of Retinal Disease: From Bench to Bedside","volume":"123","author":"Campochiaro","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.visres.2017.05.009","article-title":"The inner blood-retinal barrier: Cellular basis and development","volume":"139","author":"Ramos","year":"2017","journal-title":"Vis. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/s41565-021-00898-0","article-title":"The current landscape of nucleic acid therapeutics","volume":"16","author":"Kulkarni","year":"2021","journal-title":"Nat. Nanotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1073\/pnas.75.1.280","article-title":"Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide","volume":"75","author":"Zamecnik","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"255","DOI":"10.2165\/00003088-200241040-00002","article-title":"Fomivirsen: Clinical pharmacology and potential drug interactions","volume":"41","author":"Geary","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35888","article-title":"Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans","volume":"391","author":"Fire","year":"1998","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/s41565-019-0591-y","article-title":"The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs","volume":"14","author":"Akinc","year":"2019","journal-title":"Nat. Nanotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1089\/nat.2023.0068","article-title":"Nucleic Acid Therapeutics: Successes, Milestones, and Upcoming Innovation","volume":"34","author":"Belgrad","year":"2024","journal-title":"Nucleic Acid Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3802","DOI":"10.1016\/j.apsb.2024.05.008","article-title":"Current status and trends in small nucleic acid drug development: Leading the future","volume":"14","author":"Miao","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hassan, M.S.A., Zhong, C., Hassan, F., and Li, S.K. (2025). Targeting the Eye: RNA-Based Therapies, Interferences, and Delivery Strategies. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17101326"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.tibtech.2024.05.002","article-title":"Ocular RNA nanomedicine: Engineered delivery nanoplatforms in treating eye diseases","volume":"42","author":"Zhang","year":"2024","journal-title":"Trends Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105751","DOI":"10.1016\/j.ebiom.2025.105751","article-title":"Innovative therapies for inherited retinal dystrophies: Navigating DNA, RNA, and protein approaches","volume":"116","year":"2025","journal-title":"EBioMedicine"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"French, L.S., Mellough, C.B., Chen, F.K., and Carvalho, L.S. (2020). A Review of Gene, Drug and Cell-Based Therapies for Usher Syndrome. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.00183"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"241","DOI":"10.4062\/biomolther.2023.001","article-title":"Drug Discovery Perspectives of Antisense Oligonucleotides","volume":"31","author":"Kim","year":"2023","journal-title":"Biomol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12932","DOI":"10.1093\/nar\/gkx1073","article-title":"RNase H sequence preferences influence antisense oligonucleotide efficiency","volume":"45","author":"Kielpinski","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41573-021-00162-z","article-title":"Antisense technology: An overview and prospectus","volume":"20","author":"Crooke","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/j.1365-2710.2004.00579.x","article-title":"RNA-mediated gene silencing: Mechanisms and its therapeutic applications","volume":"29","author":"Verma","year":"2004","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1128\/MMBR.67.4.657-685.2003","article-title":"RNA interference: Biology, mechanism, and applications","volume":"67","author":"Agrawal","year":"2003","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"174178","DOI":"10.1016\/j.ejphar.2021.174178","article-title":"Awidi A: SiRNA: Mechanism of action, challenges, and therapeutic approaches","volume":"905","author":"Alshaer","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.cell.2009.01.035","article-title":"Origins and Mechanisms of miRNAs and siRNAs","volume":"136","author":"Carthew","year":"2009","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41580-018-0045-7","article-title":"Regulation of microRNA function in animals","volume":"20","author":"Gebert","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1042\/bse0540029","article-title":"Mechanism of miRNA-mediated repression of mRNA translation","volume":"54","author":"Dalmay","year":"2013","journal-title":"Essays Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.jare.2020.08.012","article-title":"Therapeutic advances of miRNAs: A preclinical and clinical update","volume":"28","author":"Chakraborty","year":"2021","journal-title":"J. Adv. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1111\/bjh.15547","article-title":"Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma","volume":"183","author":"Seto","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/wrr.12660","article-title":"A synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds","volume":"26","author":"Piper","year":"2018","journal-title":"Wound Repair Regen."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1124\/mol.117.110650","article-title":"Long Noncoding RNA LINC00657 Acting as a miR-590-3p Sponge to Facilitate Low Concentration Oxidized Low-Density Lipoprotein-Induced Angiogenesis","volume":"93","author":"Bao","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"622","DOI":"10.2174\/1389201019666180802145134","article-title":"Small Activating RNAs: Towards Development of New Therapeutic Agents and Clinical Treatments","volume":"19","author":"Li","year":"2018","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1093\/nar\/gkw076","article-title":"Small activating RNA binds to the genomic target site in a seed-region-dependent manner","volume":"44","author":"Meng","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_33","first-page":"690","article-title":"Aptamers and aptazymes: Accelerating small molecule drug discovery","volume":"5","author":"Burgstaller","year":"2002","journal-title":"Curr. Opin. Drug Discov. Dev."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Lai, B.S., and Juhas, M. (2019). Recent Advances in Aptamer Discovery and Applications. Molecules, 24.","DOI":"10.3390\/molecules24050941"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12569","DOI":"10.1002\/anie.202103027","article-title":"Multicolor Two-Photon Nanosystem for Multiplexed Intracellular Imaging and Targeted Cancer Therapy","volume":"60","author":"Wu","year":"2021","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.1021\/ja908035g","article-title":"Expanding the chemistry of DNA for in vitro selection","volume":"132","author":"Vaught","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bege, M., and Borb\u00e1s, A. (2022). The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides. Pharmaceuticals, 15.","DOI":"10.3390\/ph15080909"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.bcp.2008.11.005","article-title":"Cross-species comparison of in vivo PK\/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100","volume":"77","author":"Yu","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"375","DOI":"10.2165\/00003495-199957030-00010","article-title":"Fomivirsen","volume":"57","author":"Perry","year":"1999","journal-title":"Drugs"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s40259-022-00549-3","article-title":"Therapeutic siRNA: State-of-the-Art and Future Perspectives","volume":"36","author":"Friedrich","year":"2022","journal-title":"BioDrugs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7224","DOI":"10.1093\/nar\/gkac562","article-title":"Identification of nucleobase chemical modifications that reduce the hepatotoxicity of gapmer antisense oligonucleotides","volume":"50","author":"Yoshida","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6023","DOI":"10.1093\/nar\/gkx135","article-title":"N1-methyl-pseudouridine in mRNA enhances translation through eIF2\u03b1-dependent and independent mechanisms by increasing ribosome density","volume":"45","author":"Svitkin","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"eaaz6893","DOI":"10.1126\/sciadv.aaz6893","article-title":"Impact of mRNA chemistry and manufacturing process on innate immune activation","volume":"6","author":"Nelson","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1038\/nm.1887","article-title":"5\u2032-Triphosphate-siRNA: Turning gene silencing and Rig-I activation against melanoma","volume":"14","author":"Poeck","year":"2008","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1021\/jm049167j","article-title":"Fully 2\u2032-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA","volume":"48","author":"Allerson","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3306","DOI":"10.1093\/nar\/gkz140","article-title":"Safety evaluation of 2\u2032-deoxy-2\u2032-fluoro nucleotides in GalNAc-siRNA conjugates","volume":"47","author":"Janas","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1002\/anie.201006519","article-title":"Unique gene-silencing and structural properties of 2\u2032-fluoro-modified siRNAs","volume":"50","author":"Manoharan","year":"2011","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.1016\/j.bbamem.2010.02.012","article-title":"Morpholinos and their peptide conjugates: Therapeutic promise and challenge for Duchenne muscular dystrophy","volume":"1798","author":"Moulton","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40824-019-0156-z","article-title":"Recent advances in the development of gene delivery systems","volume":"23","author":"Sung","year":"2019","journal-title":"Biomater. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1007\/s40265-018-0983-6","article-title":"Patisiran: First Global Approval","volume":"78","author":"Hoy","year":"2018","journal-title":"Drugs"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1016\/j.ymthe.2021.05.004","article-title":"A SARS-CoV-2 targeted siRNA-nanoparticle therapy for COVID-19","volume":"29","author":"Idris","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.omtn.2016.12.003","article-title":"Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics","volume":"6","author":"Huang","year":"2017","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"16259","DOI":"10.1021\/acsomega.1c01755","article-title":"Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation","volume":"6","author":"Cui","year":"2021","journal-title":"ACS Omega"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"105864","DOI":"10.1016\/j.phrs.2021.105864","article-title":"GalNAc-siRNA conjugates: Prospective tools on the frontier of anti-viral therapeutics","volume":"173","author":"Thangamani","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.ymthe.2020.06.015","article-title":"Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug","volume":"28","author":"Debacker","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4840","DOI":"10.1093\/nar\/gkac308","article-title":"Targeted delivery to macrophages and dendritic cells by chemically modified mannose ligand-conjugated siRNA","volume":"50","author":"Uehara","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41573-020-0090-8","article-title":"Engineering precision nanoparticles for drug delivery","volume":"20","author":"Mitchell","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4789","DOI":"10.1167\/iovs.10-5891","article-title":"A lipid nanoparticle system improves siRNA efficacy in RPE cells and a laser-induced murine CNV model","volume":"52","author":"Liu","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6410","DOI":"10.1021\/acs.nanolett.9b02596","article-title":"Octopus-like Flexible Vector for Noninvasive Intraocular Delivery of Short Interfering Nucleic Acids","volume":"19","author":"Jiang","year":"2019","journal-title":"Nano Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.addr.2020.06.020","article-title":"Delivery of drugs, proteins, and nucleic acids using inorganic nanoparticles","volume":"156","author":"Luther","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41578-022-00529-7","article-title":"Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs","volume":"8","author":"Dilliard","year":"2023","journal-title":"Nat. Rev. Mater."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.jconrel.2021.06.030","article-title":"In vivo targeted delivery of nucleic acids and CRISPR genome editors enabled by GSH-responsive silica nanoparticles","volume":"336","author":"Wang","year":"2021","journal-title":"J. Control Release"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1186\/s12951-022-01570-y","article-title":"Stimuli-responsive nanoformulations for CRISPR-Cas9 genome editing","volume":"20","author":"Fang","year":"2022","journal-title":"J. Nanobiotechnol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12929-014-0108-9","article-title":"EpCAM aptamer mediated cancer cell specific delivery of EpCAM siRNA using polymeric nanocomplex","volume":"22","author":"Subramanian","year":"2015","journal-title":"J. BioMed. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"10760","DOI":"10.1021\/acsami.1c00016","article-title":"A Novel Peptide-Equipped Exosomes Platform for Delivery of Antisense Oligonucleotides","volume":"13","author":"Xu","year":"2021","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1038\/s41596-020-00466-1","article-title":"Isolation and characterization of extracellular vesicle subpopulations from tissues","volume":"16","author":"Crescitelli","year":"2021","journal-title":"Nat. Protoc."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"27066","DOI":"10.3402\/jev.v4.27066","article-title":"Biological properties of extracellular vesicles and their physiological functions","volume":"4","author":"Siljander","year":"2015","journal-title":"J. Extracell. Vesicles"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3892\/ijmm.2022.5214","article-title":"Exosome-encapsulated miR-26a attenuates aldosterone-induced tubulointerstitial fibrosis by inhibiting the CTGF\/SMAD3 signaling pathway","volume":"51","author":"Zheng","year":"2023","journal-title":"Int. J. Mol. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"12048","DOI":"10.1073\/pnas.1304718110","article-title":"Human placental trophoblasts confer viral resistance to recipient cells","volume":"110","author":"Donker","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1007\/s11095-014-1593-y","article-title":"Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio","volume":"32","author":"Yang","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.biotechadv.2017.12.010","article-title":"Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds","volume":"36","author":"Farooqi","year":"2018","journal-title":"Biotechnol. Adv."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zhang, W., Huang, Q., Xiao, W., Zhao, Y., Pi, J., Xu, H., Zhao, H., Xu, J., Evans, C.E., and Jin, H. (2020). Advances in Anti-Tumor Treatments Targeting the CD47\/SIRP\u03b1 Axis. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00018"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jconrel.2017.09.013","article-title":"Cancer-derived exosomes as a delivery platform of CRISPR\/Cas9 confer cancer cell tropism-dependent targeting","volume":"266","author":"Kim","year":"2017","journal-title":"J. Control Release"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"eabj9617","DOI":"10.1126\/sciadv.abj9617","article-title":"MiR-204-containing exosomes ameliorate GVHD-associated dry eye disease","volume":"8","author":"Zhou","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e2403935","DOI":"10.1002\/adma.202403935","article-title":"Membrane Fusion-Mediated Loading of Therapeutic siRNA into Exosome for Tissue-Specific Application","volume":"36","author":"Xie","year":"2024","journal-title":"Adv. Mater."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/ceo.14294","article-title":"Treatment of dry age-related macular degeneration: A review","volume":"51","author":"Girgis","year":"2023","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.ophtha.2020.08.027","article-title":"C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2\/3 Trial","volume":"128","author":"Jaffe","year":"2021","journal-title":"Ophthalmology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1080\/1750743X.2024.2368342","article-title":"C5 inhibitor avacincaptad pegol treatment for geographic atrophy: A comprehensive review","volume":"16","author":"Danzig","year":"2024","journal-title":"Immunotherapy"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.ophtha.2025.12.011","article-title":"Avacincaptad Pegol for Geographic Atrophy Secondary to Age-Related Macular Degeneration: Two-Year Efficacy and Safety Results from the GATHER2 Phase 3 Trial","volume":"133","author":"Khanani","year":"2026","journal-title":"Ophthalmology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.2165\/00003495-200868080-00002","article-title":"Neovascular age-related macular degeneration: Potential therapies","volume":"68","author":"Chappelow","year":"2008","journal-title":"Drugs"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.1016\/j.ymthe.2026.06.036","article-title":"Cell-penetrating asymmetric siRNA targeting MyD88 suppresses inflammasome-driven ocular degeneration and angiogenesis","volume":"34","author":"Kim","year":"2026","journal-title":"Mol. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1089\/hum.2011.145","article-title":"Asymmetric siRNA: New strategy to improve specificity and reduce off-target gene expression","volume":"23","author":"Yuan","year":"2012","journal-title":"Hum. Gene Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/s41433-023-02848-7","article-title":"Clinical proof of concept for anti-FGF2 therapy in exudative age-related macular degeneration (nAMD): Phase 2 trials in treatment-na\u00efve and anti-VEGF pretreated patients","volume":"38","author":"Pereira","year":"2024","journal-title":"Eye"},{"key":"ref_84","first-page":"3309","article-title":"First results of the phase 2 BETTER trial using intravitreal ISTH0036, a selective TGF-\u03b22 blocking antisense in AMD and DME","volume":"65","author":"Munk","year":"2024","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Dave, B., Patel, M., Suresh, S., Ginjupalli, M., Surya, A., Albdour, M., and Kooner, K.S. (2024). Wound Modulations in Glaucoma Surgery: A Systematic Review. Bioengineering, 11.","DOI":"10.3390\/bioengineering11050446"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ophtha.2025.07.039","article-title":"A Randomized Sham-Controlled Phase 2\/3 Trial of QPI-1007 for Acute Nonarteritic Anterior Ischemic Optic Neuropathy","volume":"133","author":"Levin","year":"2026","journal-title":"Ophthalmology"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Pfeiffer, N., Voykov, B., Renieri, G., Bell, K., Richter, P., Weigel, M., Thieme, H., Wilhelm, B., Lorenz, K., and Feindor, M. (2017). First-in-human phase I study of ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-\u03b22), in subjects with open-angle glaucoma undergoing glaucoma filtration surgery. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188899"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/mt.2013.217","article-title":"Phase I clinical trial of SYL040012, a small interfering RNA targeting \u03b2-adrenergic receptor 2, for lowering intraocular pressure","volume":"22","author":"Ruz","year":"2014","journal-title":"Mol. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"105115","DOI":"10.1016\/j.phrs.2020.105115","article-title":"Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy","volume":"161","author":"Rudraraju","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s13578-024-01269-7","article-title":"Microvascular destabilization and intricated network of the cytokines in diabetic retinopathy: From the perspective of cellular and molecular components","volume":"14","author":"Sheng","year":"2024","journal-title":"Cell Biosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s12974-015-0368-7","article-title":"Neuroinflammatory responses in diabetic retinopathy","volume":"12","author":"Yu","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1080\/08820538.2022.2152706","article-title":"Molecular Mediators and Regulators of Retinal Angiogenesis","volume":"38","author":"Vishwakarma","year":"2023","journal-title":"Semin. Ophthalmol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1177\/193229680900300440","article-title":"Antisense oligonucleotide therapy in diabetic retinopathy","volume":"3","author":"Hnik","year":"2009","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"101029","DOI":"10.1016\/j.preteyeres.2021.101029","article-title":"Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities","volume":"89","author":"Schneider","year":"2022","journal-title":"Prog. Retin Eye Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1038\/s41591-022-01755-w","article-title":"Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: A phase 1b\/2 trial","volume":"28","author":"Russell","year":"2022","journal-title":"Nat. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"101873","DOI":"10.1016\/j.ajoc.2023.101873","article-title":"Durable vision improvement after a single intravitreal treatment with antisense oligonucleotide in CEP290-LCA: Replication in two eyes","volume":"32","author":"Cideciyan","year":"2023","journal-title":"Am. J. Ophthalmol. Case Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1016\/j.ymthe.2021.04.024","article-title":"Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations","volume":"29","author":"Dulla","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Grainok, J., Pitout, I.L., Chen, F.K., McLenachan, S., Heath Jeffery, R.C., Mitrpant, C., and Fletcher, S. (2024). A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063391"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Banik, P., Zimmann, F., Thakur, P.K., Dudakova, L., Ve\u010derkov\u00e1, K., Kostov, O., Caruthers, M.H., Kol\u00e1\u0159, M., Krej\u010d\u00ed\u0159ov\u00e1, I., and Vajter, M. (2026). Targeted antisense oligonucleotide therapy rescues PRPF31 expression in retinitis pigmentosa caused by a splicing mutation. Mol. Ther., in press.","DOI":"10.1016\/j.ymthe.2026.05.033"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1001\/jama.2021.19963","article-title":"Dry Eye Disease: An Update in 2022","volume":"327","author":"Hakim","year":"2022","journal-title":"JAMA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1021\/acsmaterialslett.4c02327","article-title":"An Injectable Copolymer for in Situ Lubrication Effectively Relieves Dry Eye Disease","volume":"7","author":"Yang","year":"2025","journal-title":"ACS Mater. Lett."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1080\/13543784.2018.1457647","article-title":"Tivanisiran, a novel siRNA for the treatment of dry eye disease","volume":"27","author":"Bleau","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s40265-024-02031-6","article-title":"Galor A: Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease","volume":"84","author":"Locatelli","year":"2024","journal-title":"Drugs"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41392-024-02112-8","article-title":"Landscape of small nucleic acid therapeutics: Moving from the bench to the clinic as next-generation medicines","volume":"10","author":"Liu","year":"2025","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"101148","DOI":"10.1016\/j.mam.2022.101148","article-title":"RNA interference (RNAi)-based therapeutics for treatment of rare neurologic diseases","volume":"91","author":"Germain","year":"2023","journal-title":"Mol. Asp. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1080\/13543784.2020.1804853","article-title":"Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases","volume":"29","author":"Xue","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1093\/hmg\/ddn140","article-title":"Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism","volume":"17","author":"Jacobson","year":"2008","journal-title":"Hum. Mol. Genet"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ejpb.2023.10.010","article-title":"Overcoming delivery barriers for RNA therapeutics in the treatment of rheumatoid arthritis","volume":"192","author":"Zhang","year":"2023","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ajo.2010.02.006","article-title":"RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027","volume":"150","author":"Kaiser","year":"2010","journal-title":"Am. J. Ophthalmol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/IIO.0000000000000380","article-title":"Choosing Outcome Measures and Assessing Efficacy of Therapeutic Interventions in Inherited Retinal Diseases: The Importance of Natural History Studies","volume":"61","author":"Iannaccone","year":"2021","journal-title":"Int. Ophthalmol. Clin."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e01730","DOI":"10.1002\/adhm.202501730","article-title":"Nanogel-Engineered Drug Delivery Systems for Enhanced Ocular Therapeutics","volume":"14","author":"Xia","year":"2025","journal-title":"Adv. Healthc. Mater."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.drudis.2007.11.002","article-title":"Current and future ophthalmic drug delivery systems. A shift to the posterior segment","volume":"13","author":"Urtti","year":"2008","journal-title":"Drug Discov. Today"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.biopha.2004.01.007","article-title":"Nanomedicines for overcoming biological barriers","volume":"58","author":"Alonso","year":"2004","journal-title":"BioMed. Pharmacother."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0140-6736(17)31868-8","article-title":"Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: A randomised, controlled, open-label, phase 3 trial","volume":"390","author":"Russell","year":"2017","journal-title":"Lancet"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1146\/annurev.pharmtox.010909.105654","article-title":"RNA targeting therapeutics: Molecular mechanisms of antisense oligonucleotides as a therapeutic platform","volume":"50","author":"Bennett","year":"2010","journal-title":"Annu Rev. Pharmacol. Toxicol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1093\/nass\/1.1.241","article-title":"2\u2032-O,4\u2032-C-ethylene-bridged nucleic acids (ENA) with nuclease-resistance and high affinity for RNA","volume":"1","author":"Morita","year":"2001","journal-title":"Nucleic Acids Res. Suppl."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nbt1081","article-title":"Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA","volume":"23","author":"Judge","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/gim.2015.15","article-title":"Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies","volume":"17","author":"Lee","year":"2015","journal-title":"Genet. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"101416","DOI":"10.1016\/j.mam.2025.101416","article-title":"Antisense oligonucleotides for inherited retinal diseases: A comprehensive review","volume":"106","author":"Banadaki","year":"2025","journal-title":"Mol. Asp. Med."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/9\/1189\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:20:10Z","timestamp":1790050810000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/9\/1189"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":120,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["pharmaceutics18091189"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18091189","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}