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Herein ultrasmall polymeric micelles encapsulating Beva (P@Beva) are developed for noninvasive topical delivery to posterior eye tissues. Beva is efficiently loaded into 11\u00a0nm micelles fabricated via self\u2010assembly of hyperbranched amphiphilic copolymers. The neutral, brush\u2010like micelles demonstrate excellent drug encapsulation and colloidal stability. In vitro, P@Beva enhances intracellular delivery of Beva in ocular cells versus free drug. Ex vivo corneal and conjunctival\u2010sclera\u2010choroidal tissues transport after eye drops are improved 23\u2010fold and 7.9\u2010fold, respectively. Anti\u2010angiogenic bioactivity is retained with P@Beva eliciting greater inhibition of endothelial tube formation and choroid sprouting over Beva alone. Remarkably, in an oxygen\u2010induced retinopathy (OIR) model, topical P@Beva matching efficacy of intravitreal Beva injection, is the clinical standard. Comprehensive biocompatibility verifies safety. Overall, this pioneering protein delivery platform holds promise to shift paradigms from invasive intravitreal injections toward simplified, noninvasive administration of biotherapeutics targeting posterior eye diseases.<\/jats:p>","DOI":"10.1002\/adma.202314126","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T11:40:25Z","timestamp":1717155625000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Enhanced Ocular Delivery of Beva via Ultra\u2010Small Polymeric Micelles for Noninvasive Anti\u2010VEGF Therapy"],"prefix":"10.1002","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6735-5952","authenticated-orcid":false,"given":"Ruhui","family":"Yang","sequence":"first","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital School of Biomedical Engineering Wenzhou Zhejiang Province 325035 China"},{"name":"Wenzhou Key Laboratory of Perioperative Medicine University of Chinese Academy of Sciences  Wenzhou Zhejiang Province 325001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1046-0847","authenticated-orcid":false,"given":"Sicheng","family":"Tang","sequence":"additional","affiliation":[{"name":"Wenzhou Key Laboratory of Perioperative Medicine University of Chinese Academy of Sciences  Wenzhou Zhejiang Province 325001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital School of Biomedical Engineering Wenzhou Zhejiang Province 325035 China"},{"name":"Wenzhou Key Laboratory of Perioperative Medicine University of Chinese Academy of Sciences  Wenzhou Zhejiang Province 325001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaofan","family":"Jin","sequence":"additional","affiliation":[{"name":"Wenzhou Key Laboratory of Perioperative Medicine University of Chinese Academy of Sciences  Wenzhou Zhejiang Province 325001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3611-1285","authenticated-orcid":false,"given":"Yuhua","family":"Tong","sequence":"additional","affiliation":[{"name":"The Quzhou Affiliated Hospital of Wenzhou Medical University Quzhou People's Hospital Quzhou Zhejiang Province 324000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University Linhai Zhejiang 317000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0492-2913","authenticated-orcid":false,"given":"Xingjie","family":"Zan","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital School of Biomedical Engineering Wenzhou Zhejiang Province 325035 China"},{"name":"Wenzhou Key Laboratory of Perioperative Medicine University of Chinese Academy of Sciences  Wenzhou Zhejiang Province 325001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,10]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.03.026"},{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103632"},{"key":"e_1_2_8_1_3","doi-asserted-by":"publisher","DOI":"10.7150\/thno.39488"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2165\/11538130-000000000-00000"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.15217"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-013-0993-5"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2015.06.002"},{"key":"e_1_2_8_3_3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2016.04.028"},{"key":"e_1_2_8_3_4","doi-asserted-by":"publisher","DOI":"10.1007\/BF01701481"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.021"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.2016.1132696"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41433-020-0895-z"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2016.04.056"},{"key":"e_1_2_8_5_3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.07.058"},{"key":"e_1_2_8_6_1","volume":"8","author":"Solomon S. 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