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Constrained by short precorneal residence and monotherapy, DED therapies necessitate frequent dosing and polypharmacy, leaving unmet needs for prolonged ocular retention and multimodal intervention. Herein, we develop berberine (BBR)\u2010loaded dual\u2010dynamically crosslinked nanogels (BBR@MPN\u2010NGs) integrating tannic acid (TA)\u2010zinc metal\u2010polyphenol networks with carboxymethyl chitosan\/aldehyde\u2010functionalized poly(ethylene glycol) Schiff base networks, enabling a single\u2010platform multimodal therapy combining antioxidant, anti\u2010inflammatory, and lubricating capacities. Capitalizing on dual\u2010dynamic synergy, BBR@MPN\u2010NGs exhibit 1\u2010year colloidal and antioxidant stability alongside lubricity, while leveraging TA\u2010mediated adhesion and Schiff base reversibility to sustain corneal BBR exposure for 24\u00a0h, enabling once\u2010daily dosing. In murine DED models, BBR@MPN\u2010NGs outperform first\u2010line cyclosporine A and dexamethasone in promoting corneal epithelial repair and tear secretion. Mechanistically, the nanogels reprogram the pathological microenvironment by scavenging reactive oxygen species, attenuating pro\u2011inflammatory macrophage polarization, and suppressing c\u2010Jun N\u2010terminal kinase signaling to reduce pro\u2010inflammatory gene expression. Notably, the preservative\u2010free nanogels passed sterility and endotoxin testing, showing no ocular or systemic toxicity, which supports biosafety. These dual\u2010dynamically crosslinked nanogels enable reduced\u2010frequency and shortened treatment duration, offering an integrated strategy for complex ocular surface diseases requiring sustained multimodal intervention.<\/jats:p>","DOI":"10.1002\/advs.78237","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:42:37Z","timestamp":1791776557000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual\u2010Dynamically Crosslinked Nanogels Enable Prolonged Ocular Retention for Multimodal Dry Eye Therapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2571-9613","authenticated-orcid":false,"given":"Yanru","family":"Xin","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4793-1383","authenticated-orcid":false,"given":"Sisi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6865-8509","authenticated-orcid":false,"given":"Shengli","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3800-9537","authenticated-orcid":false,"given":"Jingyan","family":"Zhu","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Ocular Diseases Eye Hospital Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Wang","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Ocular Diseases Eye Hospital Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4351-4872","authenticated-orcid":false,"given":"Jianliang","family":"Shen","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Ophthalmic Drug Discovery and Medical Device Research Eye Hospital Wenzhou Medical University  Wenzhou People's Republic of China"},{"name":"Zhejiang Engineering Research Center for Tissue Repair Materials Wenzhou Institute University of Chinese Academy of Sciences  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0011-3702","authenticated-orcid":false,"given":"Qinxiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1407936"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.19963"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtos.2017.05.011"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2017.07.021"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","unstructured":"C. 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