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While timolol maleate effectively lowers IOP, it does not prevent RGC loss and suffers from poor corneal permeability and rapid clearance. This study introduces a novel dual-delivery nanovesicular system employing multifunctional spanlastics to simultaneously lower IOP and inhibit RGC apoptosis via caspase-2 gene silencing. The system comprises two distinct nanovesicle populations: (i) timolol-loaded vesicles conjugated with peptide dendrimers to enhance corneal penetration and anterior segment delivery; and (ii) siRNA-loaded vesicles targeting Caspase-2, coated with hyaluronic acid for posterior segment delivery and gene silencing. This is the first approach integrating IOP reduction with targeted genetic intervention to protect RGCs. Formulations were optimized using a Design of Experiments approach and showed desirable physicochemical properties, sustained release, improved transcorneal permeability, and 1-month stability at 4\u00a0\u00b0C. In vitro studies confirmed Caspase-2 silencing and apoptosis reduction in RGC-5 cells, while in vivo results demonstrated prolonged IOP control. Safety was confirmed via histopathological and ocular irritation assessments. This targeted, non-invasive dual-delivery platform offers a promising therapeutic strategy for comprehensive glaucoma management.<\/jats:p>","DOI":"10.1038\/s41598-025-10960-9","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T09:10:41Z","timestamp":1752829841000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Peptide dendrimer and hyaluronic acid modified nanovesicles for ocular delivery of timolol maleate and siRNA"],"prefix":"10.1038","volume":"15","author":[{"given":"Santoshi","family":"Naik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naitik","family":"Jain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagarajan","family":"Theruveethi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivas","family":"Mutalik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"10960_CR1","doi-asserted-by":"publisher","first-page":"S22","DOI":"10.1097\/WNO.0000000000000293","volume":"35","author":"HV Danesh-Meyer","year":"2015","unstructured":"Danesh-Meyer, H. 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