{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:25:01Z","timestamp":1760059501629,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["20K22713"],"award-info":[{"award-number":["20K22713"]}]},{"name":"Hoansha Foundation","award":["20K22713"],"award-info":[{"award-number":["20K22713"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Retinal diseases can result in blindness and visual impairment. They represent a significant medical burden and adversely affect life expectancy. Recently, antibody- and nucleic acid-based pharmaceuticals have increasingly been used to treat retinal diseases, with improvement or cure as the goal; however, these drugs are currently only administered by intravitreal injection. In this study, we present a novel approach to treating retinal diseases using eye drops that contain PnkRNA, a single-stranded RNA nucleic acid. PnkRNA-loaded liposomes were shown to effectively deliver retinal drugs and significantly inhibit retinal thickening in a mouse retinal-vein occlusion model. Cationic modification of the liposome surface enhanced the delivery of nucleic acids and therapeutic efficacy. Moreover, to reduce the frequency of eye-drop administration, liposomes were incorporated into the thermoresponsive gels. This formulation provided sustained retinal delivery and exhibited superior therapeutic efficacy compared with liposomal eye drops. This nucleic acid retinal delivery technology represents a significant advancement in drug-delivery technology, offering a safe and simple treatment for retinal diseases.<\/jats:p>","DOI":"10.3390\/molecules30122622","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T10:45:26Z","timestamp":1750157126000},"page":"2622","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Topical Application of RNAi Therapy Using Surface-Modified Liposomes for Treating Retinal-Vein Occlusion"],"prefix":"10.3390","volume":"30","author":[{"given":"Taishi","family":"Shiratori","sequence":"first","affiliation":[{"name":"Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaaki","family":"Ito","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anri","family":"Nishinaka","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryosuke","family":"Matsumiya","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8306-9457","authenticated-orcid":false,"given":"Eriko","family":"Yamazoe","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"},{"name":"Laboratory of Advanced Pharmaceutical Process Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideaki","family":"Hara","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3471-2412","authenticated-orcid":false,"given":"Kohei","family":"Tahara","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/S2214-109X(17)30293-0","article-title":"Vision loss expert group, magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: A systematic review and meta-analysis","volume":"5","author":"Bourne","year":"2017","journal-title":"Lancet Glob. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1097\/APO.0000000000000598","article-title":"Update on retinal vein occlusion","volume":"12","author":"Romano","year":"2023","journal-title":"Asia-Pac. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Noma, H., Yasuda, K., and Shimura, M. (2020). Cytokines and pathogenesis of central retinal vein occlusion. J. Clin. Med., 9.","DOI":"10.3390\/jcm9113457"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1097\/IAE.0b013e31821504f2","article-title":"Endophthalmitis after intravitreal injection: Prevention and management","volume":"31","author":"Wykoff","year":"2011","journal-title":"Retina"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/clpt.2008.297","article-title":"Ophthalmic drug delivery: Development and regulatory considerations","volume":"85","author":"Novack","year":"2009","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_6","unstructured":"Hori, M., Sugano, K., Kadowaki, T., Inui, K., and Hayashi, M. (2024). Handbook of Clinical Drug 2024, Jiho, Inc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.jconrel.2023.07.055","article-title":"Challenges and strategies for ocular posterior diseases therapy via non-invasive advanced drug delivery","volume":"361","author":"Qi","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"123840","DOI":"10.1016\/j.ijpharm.2024.123840","article-title":"Triamcinolone-loaded self nano-emulsifying drug delivery systems for ocular use: An alternative to invasive ocular surgeries and injections","volume":"653","author":"Dehghani","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1080\/17425247.2018.1496080","article-title":"Recent advance of nanoparticle-based topical drug delivery to the posterior segment of the eye","volume":"15","author":"Wang","year":"2018","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.exer.2016.07.003","article-title":"Size effect of rebamipide ophthalmic nanodispersions on its therapeutic efficacy for corneal wound healing","volume":"151","author":"Nagai","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jconrel.2009.02.020","article-title":"Design and evaluation of a liposomal delivery system targeting the posterior segment of the eye","volume":"136","author":"Hironaka","year":"2009","journal-title":"J. Control. Release"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.ijpharm.2012.07.024","article-title":"Liposomal diclofenac eye drop formulations targeting the retina: Formulation stability improvement using surface modification of liposomes","volume":"436","author":"Fujisawa","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejpb.2012.10.014","article-title":"Retinal drug delivery using eyedrop preparations of poly-L-lysine-modified liposomes","volume":"83","author":"Sasaki","year":"2013","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s40291-024-00722-0","article-title":"Gene therapies in clinical development to treat retinal disorders","volume":"28","author":"McClements","year":"2024","journal-title":"Mol. Diagn. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"523","DOI":"10.4155\/tde.11.20","article-title":"Polymeric vectors for ocular gene delivery","volume":"2","author":"Tamboli","year":"2011","journal-title":"Ther. Deliv."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nishida, S., Takashima, Y., Udagawa, R., Ibaraki, H., Seta, Y., and Ishihara, H. (2023). A multifunctional hybrid nanocarrier for non-invasive siRNA delivery to the retina. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020611"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Takanashi, M., Sudo, K., Ueda, S., Ohno, S., Yamada, Y., Osakabe, Y., Goto, H., Matsunaga, Y., Ishikawa, A., and Usui, Y. (2015). Novel types of small RNA exhibit sequence- and target-dependent angiogenesis suppression without activation of Toll-like receptor 3 in an age-related macular degeneration (AMD) mouse model. Mol. Ther.-Nucleic Acids, 4.","DOI":"10.1038\/mtna.2015.34"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hamasaki, T., Suzuki, H., Shirohzu, H., Matsumoto, T., D\u2019Alessandro-Gabazza, C.N., Gil-Bernabe, P., Boveda-Ruiz, D., Naito, M., Kobayashi, T., and Toda, M. (2012). Efficacy of a novel class of RNA interference therapeutic agents. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042655"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Igarashi, J., Niwa, Y., and Sugiyama, D. (2020). Research and development of oligonucleotide therapeutics in Japan for rare diseases. Future Rare Dis., 2.","DOI":"10.2217\/frd-2021-0008"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Taketani, Y., Usui, T., Toyono, T., Shima, N., Yokoo, S., Kimakura, M., Yamagami, S., Ohno, S., Onodera, R., and Tahara, K. (2016). Topical use of angiopoietin-like protein 2 RNAi-loaded lipid nanoparticles suppresses corneal neovascularization. Mol. Ther.-Nucleic Acids, 5.","DOI":"10.1038\/mtna.2016.1"},{"key":"ref_21","first-page":"3271","article-title":"Delivery of siRNA using cationic liposomes incorporating stearic acid-modified octa-arginine","volume":"36","author":"Yang","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/sj.gt.3302910","article-title":"Octaarginine-modified multifunctional envelope-type nanoparticles for gene delivery","volume":"14","author":"Khalil","year":"2007","journal-title":"Gene Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s10792-018-0820-7","article-title":"A nationwide survey of factors influencing adherence to ocular hypotensive eyedrops in Japan","volume":"39","author":"Tsumura","year":"2019","journal-title":"Int. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1016\/S0032-3861(99)00413-9","article-title":"Thermogelation of methylcellulose: Rheological considerations","volume":"41","author":"Desbrieres","year":"2000","journal-title":"Polymer"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Fuma, S., Nishinaka, A., Inoue, Y., Tsuruma, K., Shimazawa, M., Kondo, M., and Hara, H. (2017). A pharmacological approach in newly established retinal vein occlusion model. Sci. Rep., 7.","DOI":"10.1038\/srep43509"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yi, Y., Pyun, S.H., Kim, C.Y., Yun, G., Kang, E., Heo, S., Ullah, I., and Lee, S.K. (2024). Eye drop with Fas-blocking peptide attenuates age-related macular degeneration. Cells, 13.","DOI":"10.3390\/cells13060548"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/j.addr.2005.09.004","article-title":"Topical and systemic drug delivery to the posterior segments","volume":"57","author":"Hughes","year":"2005","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1167\/iovs.09-4244","article-title":"The safety of intraocular linezolid in rabbits","volume":"51","author":"Duke","year":"2010","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_29","unstructured":"Takeuchi, M. (2013). Farumashia, The Pharmaceutical Society of Japan."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1248\/cpb.58.247","article-title":"Effect of D-sorbitol on the thermal gelation of methylcellulose formulations for drug delivery","volume":"58","author":"Itoh","year":"2010","journal-title":"Chem. Pharm. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.actbio.2018.04.037","article-title":"Injectable drug depot engineered to release multiple ophthalmic therapeutic agents with precise time profiles for postoperative treatment following ocular surgery","volume":"73","author":"Mohammadi","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_32","unstructured":"Hishikawa, Y., Kakino, Y., Furukawa, H., Tahara, K., and Takeuchi, H. (2015). Kobunshi Ronbunshu, Society of Polymer Science."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1124\/jpet.122.001563","article-title":"Beyond VEGF: Targeting inflammation and other pathways for treatment of retinal disease","volume":"386","author":"Muniyandi","year":"2023","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4701","DOI":"10.1167\/iovs.18-23994","article-title":"Pathophysiological role of VEGF on retinal edema and nonperfused areas in mouse eyes with retinal vein occlusion","volume":"59","author":"Nishinaka","year":"2018","journal-title":"Investig. Opthalmol. Vis. Sci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/12\/2622\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:53:48Z","timestamp":1760032428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/12\/2622"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,17]]},"references-count":34,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["molecules30122622"],"URL":"https:\/\/doi.org\/10.3390\/molecules30122622","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2025,6,17]]}}}