{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:28:52Z","timestamp":1790188132863,"version":"4.1.0"},"reference-count":125,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Age-related macular degeneration (AMD) is a degenerative eye disease that is the leading cause of irreversible vision loss in people 50 years and older. Today, the most common treatment for AMD involves repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs. However, the existing expensive therapies not only cannot cure this disease, they also produce a variety of side effects. For example, the number of injections increases the cumulative risk of endophthalmitis and other complications. Today, a single intravitreal injection of gene therapy products can greatly reduce the burden of treatment and improve visual effects. In addition, the latest innovations in nanotherapy provide the best drug delivery alternative for the treatment of AMD. In this review, we discuss the development of nano-drug delivery systems and gene therapy strategies for AMD in recent years. In addition, we discuss some novel targeting strategies and the potential application of these delivery methods in the treatment of AMD. Finally, we also propose that the combination of CRISPR\/Cas9 technology with a new non-viral delivery system may be promising as a therapeutic strategy for the treatment of AMD.<\/jats:p>","DOI":"10.3390\/pharmaceutics13122035","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T02:34:05Z","timestamp":1638326045000},"page":"2035","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Nanotechnology for Age-Related Macular Degeneration"],"prefix":"10.3390","volume":"13","author":[{"given":"Bo","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The Second Hospital of Jilin University, Changchun 130012, China"},{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-7409","authenticated-orcid":false,"given":"Shixin","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6199-9311","authenticated-orcid":false,"given":"Fengying","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Jilin University, Changchun 130012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-4342","authenticated-orcid":false,"given":"Wenhua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Hospital of Jilin University, Changchun 130012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e144","DOI":"10.1016\/S2214-109X(20)30489-7","article-title":"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","volume":"9","author":"Steinmetz","year":"2021","journal-title":"Lancet Glob. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(18)31550-2","article-title":"Age-related macular degeneration","volume":"392","author":"Mitchell","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e888","DOI":"10.1016\/S2214-109X(17)30293-0","article-title":"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_4","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1021\/acs.jproteome.8b00877","article-title":"Urine Nuclear Magnetic Resonance (NMR) Metabolomics in Age-Related Macular Degeneration","volume":"18","author":"Lains","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ijpharm.2021.121105","article-title":"Recent advances in ophthalmic preparations: Ocular barriers, dosage forms and routes of administration","volume":"608","author":"Maulvi","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Varela-Fernandez, R., Diaz-Tome, V., Luaces-Rodriguez, A., Conde-Penedo, A., Garcia-Otero, X., Luzardo-Alvarez, A., Fernandez-Ferreiro, A., and Otero-Espinar, F.J. (2020). Drug Delivery to the Posterior Segment of the Eye: Biopharmaceutic and Pharmacokinetic Considerations. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12030269"},{"key":"ref_7","first-page":"182","article-title":"Hypoxia inducible factor-1 alpha is increased in ischemic retina: Temporal and spatial correlation with VEGF expression","volume":"40","author":"Ozaki","year":"1999","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1038\/eye.2017.6","article-title":"One-year real-world outcomes in patients receiving fixed-dosing aflibercept for neovascular age related macular degeneration","volume":"31","author":"Almuhtaseb","year":"2017","journal-title":"Eye"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1021\/acs.molpharmaceut.6b00335","article-title":"PLGA Microparticles Entrapping Chitosan-Based Nanoparticles for the Ocular Delivery of Ranibizumab","volume":"13","author":"Elsaid","year":"2016","journal-title":"Mol. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1590\/s2175-97902020000118171","article-title":"Preparation and in vitro characterization of monoclonal antibody ranibizumab conjugated magnetic nanoparticles for ocular drug delivery","volume":"56","author":"Ayata","year":"2020","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jddst.2017.01.004","article-title":"Ranibizumab biosimilar\/polyethyleneglycol-conjugated gold nanoparticles as a novel drug delivery platform for age-related macular degeneration","volume":"38","author":"Hoshikawa","year":"2017","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.jphotobiol.2018.04.033","article-title":"Development of facile drug delivery platform of ranibizumab fabricated PLGA-PEGylated magnetic nanoparticles for age-related macular degeneration therapy","volume":"183","author":"Yan","year":"2018","journal-title":"J. Photochem. Photobiol. B-Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1098\/rsob.170219","article-title":"Angiogenesis revisited from a metabolic perspective: Role and therapeutic implications of endothelial cell metabolism","volume":"7","author":"Draoui","year":"2017","journal-title":"Open Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1161\/01.CIR.0000015856.84385.E9","article-title":"Angiostatin inhibits coronary angiogenesis during impaired production of nitric oxide","volume":"105","author":"Matsunaga","year":"2002","journal-title":"Circulation"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Du, W., Ren, L., Hamblin, M.H., and Fan, Y.B. (2021). Endothelial Cell Glucose Metabolism and Angiogenesis. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020147"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.cmet.2020.03.009","article-title":"Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis","volume":"31","author":"Rohlenova","year":"2020","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.cmet.2013.08.001","article-title":"Role of Endothelial Cell Metabolism in Vessel Sprouting","volume":"18","author":"Georgiadou","year":"2013","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cohen, E.B., Geck, R.C., and Toker, A. (2020). Metabolic pathway alterations in microvascular endothelial cells in response to hypoxia. PLoS ONE, 15.","DOI":"10.1101\/2020.04.08.031633"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nm.4059","article-title":"Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1","volume":"22","author":"Joyal","year":"2016","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.cmet.2018.07.019","article-title":"Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation","volume":"28","author":"Bruning","year":"2018","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/nature14362","article-title":"Fatty acid carbon is essential for dNTP synthesis in endothelial cells","volume":"520","author":"Schoors","year":"2015","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.15252\/embj.201695518","article-title":"Role of glutamine and interlinked asparagine metabolism in vessel formation","volume":"36","author":"Huang","year":"2017","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1002\/jcp.21698","article-title":"Oxidative Stress Promotes Ocular Neovascularization of the article","volume":"219","author":"Dong","year":"2009","journal-title":"J. Cell. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1056\/NEJMra062326","article-title":"Mechanisms of disease: Age-related macular degeneration","volume":"355","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Dammak, A., Huete-Toral, F., Carpena-Torres, C., Martin-Gil, A., Pastrana, C., and Carracedo, G. (2021). From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13091376"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S1350-9462(00)00027-6","article-title":"Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease","volume":"20","author":"Yu","year":"2001","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.mam.2012.03.009","article-title":"Consequences of oxidative stress in age-related macular degeneration","volume":"33","author":"Jarrett","year":"2012","journal-title":"Mol. Asp. Med."},{"key":"ref_28","first-page":"353","article-title":"Age-related macular degeneration (AMD): Pathogenesis and therapy","volume":"58","author":"Nowak","year":"2006","journal-title":"Pharmacol. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.arr.2009.01.001","article-title":"Heat shock proteins as gatekeepers of proteolytic pathways-Implications for age-related macular degeneration (AMD)","volume":"8","author":"Kaarniranta","year":"2009","journal-title":"Ageing Res. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/jcp.20439","article-title":"Effects of different types of oxidative stress in RPE cells","volume":"206","author":"Lu","year":"2006","journal-title":"J. Cell. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"809","DOI":"10.2169\/internalmedicine.45.1765","article-title":"Mitochondrial oxidative stress and heart failure","volume":"45","author":"Tsutsui","year":"2006","journal-title":"Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"646354","DOI":"10.1155\/2012\/646354","article-title":"Oxidative stress, mitochondrial dysfunction, and aging","volume":"2012","author":"Cui","year":"2012","journal-title":"J. Signal Transduct."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1517\/14728222.2013.818657","article-title":"The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: Peripheral and central mechanisms as therapeutic targets?","volume":"17","author":"Meeus","year":"2013","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"930671","DOI":"10.1155\/2014\/930671","article-title":"Age-Related Macular Degeneration in the Aspect of Chronic Low-Grade Inflammation (Pathophysiological ParaInflammation)","volume":"2014","author":"Nita","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.preteyeres.2009.11.003","article-title":"The pivotal role of the complement system in aging and age-related macular degeneration: Hypothesis re-visited","volume":"29","author":"Anderson","year":"2010","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4487","DOI":"10.1007\/s00018-021-03796-9","article-title":"The complement system in age-related macular degeneration","volume":"78","author":"Armento","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.3389\/fimmu.2019.01007","article-title":"The Challenges and Promise of Complement Therapeutics for Ocular Diseases","volume":"10","author":"Park","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1159\/000099293","article-title":"Inflammation in dry age-related macular degeneration","volume":"221","author":"Rodrigues","year":"2007","journal-title":"Ophthalmologica"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0002-9394(02)01624-0","article-title":"Perspective\u2014A role for local inflammation in the formation of drusen in the aging eye","volume":"134","author":"Anderson","year":"2002","journal-title":"Am. J. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.exer.2014.02.001","article-title":"Cholesterol-poly(ethylene) glycol nanocarriers for the transscleral delivery of sirolimus","volume":"121","author":"Elsaid","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ijpharm.2018.05.056","article-title":"Smart liposomal drug delivery for treatment of oxidative stress model in human embryonic stem cell-derived retinal pigment epithelial cells","volume":"548","author":"Behroozi","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"16803","DOI":"10.1038\/s41598-017-16791-7","article-title":"Characterization of liposomal carriers for the trans-scleral transport of Ranibizumab","volume":"7","author":"Joseph","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1080\/10717544.2018.1474967","article-title":"Multivesicular liposomes for sustained release of bevacizumab in treating laser-induced choroidal neovascularization","volume":"25","author":"Mu","year":"2018","journal-title":"Drug Deliv."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.jddst.2018.07.003","article-title":"Rational design of liposomes for sustained release drug delivery of bevacizumab to treat ocular angiogenesis","volume":"47","author":"Karumanchi","year":"2018","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Platania, C.B.M., Fisichella, V., Fidilio, A., Geraci, F., Lazzara, F., Leggio, G.M., Salomone, S., Drago, F., Pignatello, R., and Caraci, F. (2017). Topical Ocular Delivery of TGF-beta 1 to the Back of the Eye: Implications in Age-Related Neurodegenerative Diseases. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102076"},{"key":"ref_46","first-page":"2613","article-title":"Efficient downregulation of VEGF in retinal pigment epithelial cells by integrin ligand-labeled liposome-mediated siRNA delivery","volume":"8","author":"Chen","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1248\/yakushi.12-00234-3","article-title":"Non-Invasive Ophthalmic Liposomes for Nucleic Acid Delivery to Posterior Segment of Eye","volume":"132","author":"Takashima","year":"2012","journal-title":"Yakugaku Zasshi-J. Pharm. Soc. Jpn."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jconrel.2020.11.053","article-title":"In vivo fate of liposomes after subconjunctival ocular delivery","volume":"329","author":"Chaw","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"326497","DOI":"10.1155\/2011\/326497","article-title":"Liposomes for use in gene delivery","volume":"2011","author":"Balazs","year":"2011","journal-title":"J. Drug Deliv."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1002\/ijch.201300055","article-title":"Gene Delivery by Liposomes","volume":"53","author":"Golomb","year":"2013","journal-title":"Isr. J. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1208\/s12249-014-0100-4","article-title":"Novel Dexamethasone-Loaded Nanomicelles for the Intermediate and Posterior Segment Uveitis","volume":"15","author":"Vaishya","year":"2014","journal-title":"AAPS Pharmscitech"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.ejpb.2014.12.010","article-title":"Micelle formulation of hexadecyloxypropyl-cidofovir (HDP-CDV) as an intravitreal long-lasting delivery system","volume":"89","author":"Ma","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1208\/s12249-019-1404-1","article-title":"Self-Assembling Topical Nanomicellar Formulation to Improve Curcumin Absorption Across Ocular Tissues","volume":"20","author":"Alshamrani","year":"2019","journal-title":"AAPS Pharmscitech"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Gote, V., Mandal, A., Alshamrani, M., and Pal, D. (2020). Self-Assembling Tacrolimus Nanomicelles for Retinal Drug Delivery. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12111072"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1002\/wnan.1272","article-title":"Controlled ocular drug delivery with nanomicelles","volume":"6","author":"Vaishya","year":"2014","journal-title":"Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jconrel.2011.11.022","article-title":"Ocular antisense oligonucleotide delivery by cationic nanoemulsion for improved treatment of ocular neovascularization: An in-vivo study in rats and mice","volume":"160","author":"Hagigit","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3712","DOI":"10.1080\/10717544.2016.1223225","article-title":"Development of loteprednol etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for sustained delivery and enhanced ocular bioavailability","volume":"23","author":"Patel","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1080\/17425247.2020.1735348","article-title":"Penetratin-modified lutein nanoemulsion in-situ gel for the treatment of age-related macular degeneration","volume":"17","author":"Ge","year":"2020","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jddst.2016.10.009","article-title":"Preparation and characterization of a lutein loading nanoemulsion system for ophthalmic eye drops","volume":"36","author":"Lim","year":"2016","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6172","DOI":"10.1021\/acsomega.0c05535","article-title":"Redox-Responsive Hyaluronic Acid-Based Nanogels for the Topical Delivery of the Visual Chromophore to Retinal Photoreceptors","volume":"6","author":"Laradji","year":"2021","journal-title":"ACS Omega"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3805967","DOI":"10.1155\/2020\/3805967","article-title":"Evaluations of the Chuanqi Ophthalmic Microemulsion In Situ Gel on Dry Age-Related Macular Degeneration Treatment","volume":"2020","author":"Du","year":"2020","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1080\/10717540802689008","article-title":"Ophthalmic controlled release in situ gelling systems for ciprofloxacin based on polymeric carriers","volume":"16","year":"2009","journal-title":"Drug Deliv."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.jconrel.2020.10.025","article-title":"Therapeutic nanoemulsions in ophthalmic drug administration: Concept in formulations and characterization techniques for ocular drug delivery","volume":"328","author":"Singh","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1615\/CritRevTherDrugCarrierSyst.v26.i1.30","article-title":"In Situ Gelling Polymers in Ocular Drug Delivery Systems: A Review","volume":"26","author":"Mundada","year":"2009","journal-title":"Crit. Rev. Ther. Drug Carr. Syst."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Bolla, P.K., Gote, V., Singh, M., Patel, M., Clark, B.A., and Renukuntla, J. (2020). Lutein-Loaded, Biotin-Decorated Polymeric Nanoparticles Enhance Lutein Uptake in Retinal Cells. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12090798"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1089\/adt.2019.920","article-title":"Axitinib-Loaded Poly(Lactic-Co-Glycolic Acid) Nanoparticles for Age-Related Macular Degeneration: Formulation Development and In Vitro Characterization","volume":"17","author":"Narvekar","year":"2019","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"8819","DOI":"10.2147\/IJN.S217038","article-title":"Anti-Angiogenic Activity Of Bevacizumab-Bearing Dexamethasone-Loaded PLGA Nanoparticles For Potential Intravitreal Applications","volume":"14","author":"Liu","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"54","DOI":"10.2174\/1874364101206010054","article-title":"Controlled release of bevacizumab through nanospheres for extended treatment of age-related macular degeneration","volume":"6","author":"Li","year":"2012","journal-title":"Open Ophthalmol. J."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Zhang, L.L., Si, T., Fischer, A.J., Letson, A., Yuan, S., Roberts, C.J., and Xu, R.X. (2015). Coaxial Electrospray of Ranibizumab-Loaded Microparticles for Sustained Release of Anti-VEGF Therapies. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135608"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3736","DOI":"10.1038\/s41598-017-03959-4","article-title":"A new paradigm for antiangiogenic therapy through controlled release of bevacizumab from PLGA nanoparticles","volume":"7","author":"Sousa","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1002\/jbm.a.35446","article-title":"Albuminated PLGA nanoparticles containing bevacizumab intended for ocular neovascularization treatment","volume":"103","author":"Varshochian","year":"2015","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3562","DOI":"10.1167\/iovs.02-1068","article-title":"Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles","volume":"44","author":"Bourges","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.jconrel.2009.10.031","article-title":"Nanoparticle-integrin antagonist C16Y peptide treatment of choroidal neovascularization in rats","volume":"142","author":"Kim","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/s41467-019-08690-4","article-title":"Intravenous treatment of choroidal neovascularization by photo-targeted nanoparticles","volume":"10","author":"Wang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3109\/10717544.2010.483257","article-title":"Solid lipid nanoparticles for ocular drug delivery","volume":"17","author":"Seyfoddin","year":"2010","journal-title":"Drug Deliv."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"244","DOI":"10.2174\/156720110791561008","article-title":"Development and Evaluation of Novel Polymeric Nanoparticles of Brimonidine Tartrate","volume":"7","author":"Singh","year":"2010","journal-title":"Curr. Drug Deliv."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2006.10.044","article-title":"Cyclodextrins and their pharmaceutical applications","volume":"329","author":"Loftsson","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.exer.2015.03.023","article-title":"Topical cyclodextrin reduces amyloid beta and inflammation improving retinal function in ageing mice","volume":"135","author":"Kam","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1111\/bph.15209","article-title":"2-Hydroxypropyl-beta-cyclodextrin reduces retinal cholesterol in wild-type and Cyp27a1(\u2212\/\u2212)Cyp46a1(\u2212\/\u2212) mice with deficiency in the oxysterol production","volume":"178","author":"Mast","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"351","DOI":"10.2174\/1567201043334623","article-title":"Role of cyclodextrins in ophthalmics","volume":"1","author":"Kaur","year":"2004","journal-title":"Curr. Drug Deliv."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1038\/sj.gt.3302579","article-title":"Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: A long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity","volume":"12","author":"Marano","year":"2005","journal-title":"Gene Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1111\/jphp.12587","article-title":"Dexamethasone\u2014PAMAM dendrimer conjugates for retinal delivery: Preparation, characterization and in vivo evaluation","volume":"68","author":"Yavuz","year":"2016","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12951-019-0498-7","article-title":"Liposomes for effective drug delivery to the ocular posterior chamber","volume":"17","author":"Lai","year":"2019","journal-title":"J. Nanobiotechnol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1248\/bpb.33.1371","article-title":"Effect of Poly(amidoamine) Dendrimers on Corneal Penetration of Puerarin","volume":"33","author":"Yao","year":"2010","journal-title":"Biol. Pharm. Bull."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"57710","DOI":"10.1021\/acsami.0c17296","article-title":"Ophthalmic Drops with Nanoparticles Derived from a Natural Product for Treating Age-Related Macular Degeneration","volume":"12","author":"Xin","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3109\/10837450.2014.965326","article-title":"Triamcinolone acetonide nanoparticles incorporated in thermoreversible gels for age-related macular degeneration","volume":"21","author":"Hirani","year":"2016","journal-title":"Pharm. Dev. Technol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"14573","DOI":"10.1038\/s41598-019-51151-7","article-title":"Light-induced Nrf2(\u2212\/\u2212) mice as atrophic age-related macular degeneration model and treatment with nanoceria laden injectable hydrogel","volume":"9","author":"Wang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1080\/02713683.2017.1302590","article-title":"In Vivo Efficacy of an Injectable Microsphere-Hydrogel Ocular Drug Delivery System","volume":"42","author":"Osswald","year":"2017","journal-title":"Curr. Eye Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.3109\/02713683.2015.1101140","article-title":"Controlled and Extended In Vitro Release of Bioactive Anti-Vascular Endothelial Growth Factors from a Microsphere-Hydrogel Drug Delivery System","volume":"41","author":"Osswald","year":"2016","journal-title":"Curr. Eye Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1007\/s10439-015-1314-7","article-title":"Controlled and Extended Release of a Model Protein from a Microsphere-Hydrogel Drug Delivery System","volume":"43","author":"Osswald","year":"2015","journal-title":"Ann. Biomed. Eng."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"djw183","DOI":"10.1093\/jnci\/djw183","article-title":"Inactivation of Cancer Mutations Utilizing CRISPR\/Cas9","volume":"109","author":"Gebler","year":"2017","journal-title":"JNCI-J. Natl. Cancer Inst."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"30","DOI":"10.3389\/fnmol.2016.00030","article-title":"CRISPR\/Cas9: Implications for Modeling and Therapy of Neurodegenerative Diseases","volume":"9","author":"Yang","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"McAndrews, K.M., Xiao, F., Chronopoulos, A., LeBleu, V.S., Kugeratski, F.G., and Kalluri, R. (2021). Exosome-mediated delivery of CRISPR\/Cas9 for targeting of oncogenic KrasG12D in pancreatic cancer. Life Sci. Alliance, 4.","DOI":"10.26508\/lsa.202000875"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s41021-021-00188-0","article-title":"New insights on CRISPR\/Cas9-based therapy for breast Cancer","volume":"43","author":"Sabit","year":"2021","journal-title":"Genes Environ."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s11427-017-9032-4","article-title":"CRISPR\/Cas9-mediated correction of human genetic disease","volume":"60","author":"Men","year":"2017","journal-title":"Sci. China-Life Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"108482","DOI":"10.1016\/j.exer.2021.108482","article-title":"RNA therapeutics in ophthalmology-translation to clinical trials","volume":"205","author":"Gupta","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5490","DOI":"10.1167\/iovs.16-20296","article-title":"Genomic Disruption of VEGF-A Expression in Human Retinal Pigment Epithelial Cells Using CRISPR-Cas9 Endonuclease","volume":"57","author":"Yiu","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1101\/gr.219089.116","article-title":"Genome surgery using Cas9 ribonucleoproteins for the treatment of age-related macular degeneration","volume":"27","author":"Kim","year":"2017","journal-title":"Genome Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41467-017-00140-3","article-title":"Genome editing abrogates angiogenesis in vivo","volume":"8","author":"Huang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"6082","DOI":"10.1167\/iovs.17-21902","article-title":"AAV-CRISPR\/Cas9-Mediated Depletion of VEGFR2 Blocks Angiogenesis In Vitro","volume":"58","author":"Wu","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1136\/jmedgenet-2019-106473","article-title":"Gene editing prospects for treating inherited retinal diseases","volume":"57","author":"Benati","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1016\/j.cell.2013.08.021","article-title":"Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity","volume":"154","author":"Ran","year":"2013","journal-title":"Cell"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1038\/s41591-018-0137-0","article-title":"A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human hematopoietic stem and progenitor cells","volume":"24","author":"Vakulskas","year":"2018","journal-title":"Nat. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.1016\/j.celrep.2017.08.075","article-title":"The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes","volume":"20","author":"Merienne","year":"2017","journal-title":"Cell Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jconrel.2017.09.012","article-title":"Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications","volume":"266","author":"Liu","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41434-021-00239-9","article-title":"Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells","volume":"28","author":"Dreismann","year":"2021","journal-title":"Gene Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/s41551-020-00656-y","article-title":"Lentiviral delivery of co-packaged Cas9 mRNA and a Vegfa-targeting guide RNA prevents wet age-related macular degeneration in mice","volume":"5","author":"Ling","year":"2021","journal-title":"Nat. Biomed. Eng."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.omtm.2020.01.006","article-title":"Factors Impacting Efficacy of AAV-Mediated CRISPR-Based Genome Editing for Treatment of Choroidal Neovascularization","volume":"17","author":"Chung","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cobme.2018.08.003","article-title":"Adeno-associated virus-mediated delivery of CRISPR-Cas9 for genome editing in the central nervous system","volume":"7","author":"Fuentes","year":"2018","journal-title":"Curr. Opin. Biomed. Eng."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1021\/pr400751k","article-title":"Exosomal Proteins in the Aqueous Humor as Novel Biomarkers in Patients with Neovascular Age-related Macular Degeneration","volume":"13","author":"Kang","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1016\/j.yexcr.2013.05.005","article-title":"Retinal pigment epithelium (RPE) exosomes contain signaling phosphoproteins affected by oxidative stress","volume":"319","author":"Biasutto","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"28058","DOI":"10.1074\/jbc.M113.470765","article-title":"Exosomes from Retinal Astrocytes Contain Antiangiogenic Components That Inhibit Laser-induced Choroidal Neovascularization","volume":"288","author":"Hajrasouliha","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Duan, L., Ouyang, K., Wang, J.H., Xu, L.M., Xu, X., Wen, C.I., Xie, Y.X., Liang, Y.J., and Xia, J. (2021). Exosomes as Targeted Delivery Platform of CRISPR\/Cas9 for Therapeutic Genome Editing. ChemBioChem.","DOI":"10.1002\/cbic.202100359"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3650","DOI":"10.1021\/acs.molpharmaceut.5b00364","article-title":"Exogenous DNA Loading into Extracellular Vesicles via Electroporation is Size-Dependent and Enables Limited Gene Delivery","volume":"12","author":"Lamichhane","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1016\/j.celrep.2018.02.014","article-title":"A Single Administration of CRISPR\/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing","volume":"22","author":"Finn","year":"2018","journal-title":"Cell Rep."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1021\/acs.bioconjchem.8b00856","article-title":"Synthesis and Evaluation of pH-Sensitive Multifunctional Lipids for Efficient Delivery of CRISPR\/Cas9 in Gene Editing","volume":"30","author":"Sung","year":"2019","journal-title":"Bioconjug. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1089\/jop.2012.0128","article-title":"Lipid Nanoparticles as Drug\/Gene Delivery Systems to the Retina","volume":"29","author":"Delgado","year":"2013","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"379","DOI":"10.3390\/jfb6020379","article-title":"Lipid Nanoparticles for Ocular Gene Delivery","volume":"6","author":"Wang","year":"2015","journal-title":"J. Funct. Biomater."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1007\/s00417-020-04797-3","article-title":"Inhibition of retinal neovascularization by VEGF siRNA delivered via bioreducible lipid-like nanoparticles","volume":"258","author":"Wang","year":"2020","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1080\/10717544.2018.1474964","article-title":"Delivering CRISPR: A review of the challenges and approaches","volume":"25","author":"Lino","year":"2018","journal-title":"Drug Deliv."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.exer.2015.09.005","article-title":"Topical application of a G-Quartet aptamer targeting nucleolin attenuates choroidal neovascularization in a model of age-related macular degeneration","volume":"140","author":"Leaderer","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"107977","DOI":"10.1016\/j.exer.2020.107977","article-title":"Corneal neovascularization is inhibited with nucleolin-binding aptamer, AS1411","volume":"193","author":"Rebollo","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_123","unstructured":"(2020). Evaluation of intracellular uptake of cyclic RGD peptides in integrin \u03b1v\u03b23-expressing tumor cells. J. Radiopharm. Mol. Probes, 6, 34\u201343. Available online: https:\/\/kmbase.medric.or.kr\/Main.aspx?d=KMBASE&i=1145520200060020034&m=VIEW."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/gt.2008.185","article-title":"Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV","volume":"16","author":"Singh","year":"2009","journal-title":"Gene Ther."},{"key":"ref_125","first-page":"4952","article-title":"Development and Evaluation of a polysiRNA delivery system to the retina","volume":"55","author":"Sim","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/12\/2035\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:37:20Z","timestamp":1760168240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/12\/2035"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,29]]},"references-count":125,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["pharmaceutics13122035"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13122035","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,29]]}}}