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Here, we introduce a noninvasive therapeutic strategy based on stereospecific peptide\u2013polysaccharide conjugates (PPC) for efficient nAMD treatment. A controllable synthetic strategy was established to generate stereospecific L-PPC and D-PPC, among which D-PPC displayed pronounced chirality-dependent bioactivity, characterized by high-affinity binding to integrin receptors and enhanced inhibition of endothelial\/epithelial cell proliferation and migration. Following topical administration, D-PPC efficiently overcame ocular barriers and penetrated choroidal lesions while markedly suppressing pathological angiogenesis in a laser-induced choroidal neovascularization mouse model, comparable to that of intravitreal ranibizumab. We elucidated that stereospecific D-PPC modulates key molecular programs in vivo, including T-cell receptor signaling and cell adhesion molecule pathways. Notably, D-PPC exhibited no detectable ocular or systemic toxicity. This study establishes chirality-engineered peptide\u2013polysaccharide conjugates as a noninvasive and effective therapeutic for posterior ocular diseases, providing a structural and mechanistic blueprint for future translational ophthalmic applications.<\/jats:p>","DOI":"10.1021\/jacs.6c05947","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:02:06Z","timestamp":1786435326000},"page":"35467-35483","source":"Crossref","is-referenced-by-count":0,"title":["Stereospecific\nPeptide\u2013Polysaccharide Conjugates\nEnable Noninvasive Therapy of Neovascular Age-Related Macular Degeneration"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4792-0915","authenticated-orcid":true,"given":"Yachao","family":"Li","sequence":"first","affiliation":[{"name":"Hunan University , , , ,","place":["Changsha, Hunan, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyan","family":"Li","sequence":"additional","affiliation":[{"name":"The Second Xiangya Hospital of Central South University , , , ,","place":["Changsha, Hunan, China, 410011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5213-2461","authenticated-orcid":true,"given":"Dongzhe","family":"Zou","sequence":"additional","affiliation":[{"name":"Hunan University , , , ,","place":["Changsha, Hunan, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zenan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Hunan University , , , ,","place":["Changsha, Hunan, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beiling","family":"Guo","sequence":"additional","affiliation":[{"name":"Hunan University , , , ,","place":["Changsha, Hunan, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wensheng","family":"Gong","sequence":"additional","affiliation":[{"name":"Hunan University , , , ,","place":["Changsha, Hunan, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kefurong","family":"Deng","sequence":"additional","affiliation":[{"name":"Hunan University , , , ,","place":["Changsha, Hunan, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zicong","family":"Wang","sequence":"additional","affiliation":[{"name":"The Second Xiangya Hospital of Central South University , , , ,","place":["Changsha, Hunan, China, 410011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Second Xiangya Hospital of Central South University , , , ,","place":["Changsha, Hunan, China, 410011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8948-1108","authenticated-orcid":true,"given":"Yedi","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Second Xiangya Hospital of Central South University , , , ,","place":["Changsha, Hunan, China, 410011"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-0848","authenticated-orcid":true,"given":"Xianghui","family":"Xu","sequence":"additional","affiliation":[{"name":"Hunan University , , , ,","place":["Changsha, Hunan, China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"issue":"6","key":"2026090104513164300_cit1","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1056\/NEJMcp2102061","article-title":"Age-Related\nMacular Degeneration","volume":"385","author":"Apte","year":"2021","journal-title":"N. 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