miR-15a-5p outperforms anti-VEGF drug in ocular neovascularization by providing dual anti-angiogenic and neuroprotective effects.

Overview

1. Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
2. Tianjin Eye Hospital, Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Nankai University Affiliated Tianjin Eye Hospital; Clinical College of Ophthalmology, Tianjin Medical University; Tianjin, China

Abstract

Background: Pathological ocular neovascularization is a major driver of vision-threatening retinal diseases. This study aimed to investigate the role and therapeutic potential of miR-15a-5p in ocular neovascular disorders.

Methods: miR-15a-5p expression levels were assessed in intraocular fluids from patients with ocular neovascular diseases. Functional assays were performed in retinal endothelial cells under pathological conditions to evaluate proliferation and endothelial-to-mesenchymal transition. In vivo, miR-15a-5p was delivered via intravitreal injection in oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) mouse models. Therapeutic effects on pathological neovascularization were analyzed and compared with anti-VEGF treatment, including assessments of retinal structural integrity, retinal function, gliosis, and fibrotic changes. miR-15a-5p–knockout mice were used to examine retinal vascular developmental abnormalities and enhanced neovascular responses following miR-15a-5p deficiency. Safety evaluations of systemic and ocular administration were performed in both healthy and neovascularized mice. Mechanistic studies investigated whether miR-15a-5p directly targeted VEGF and Smad2.

Results: miR-15a-5p was significantly upregulated in intraocular fluids from patients with ocular neovascular diseases. Overexpression of miR-15a-5p inhibited retinal endothelial cell proliferation and endothelial-to-mesenchymal transition in vitro. In OIR and CNV models, miR-15a-5p treatment reduced retinal neovascularization, decreased reactive gliosis, and maintained retinal thickness and electrophysiological function. In miR-15a-5p–knockout mice, loss of miR-15a-5p impaired normal retinal vascular development. Mechanistically, miR-15a-5p directly targeted VEGF and Smad2, modulating angiogenic and fibrotic pathways. Compared with anti-VEGF therapy, miR-15a-5p demonstrated stronger anti-fibrotic and neuroprotective effects without affecting postnatal development or systemic metabolism. No ocular or systemic toxicity was observed at therapeutic doses.

Conclusions: miR-15a-5p regulates angiogenesis and fibrosis by targeting VEGF and Smad2. These findings suggest that miR-15a-5p is a promising therapeutic candidate for the treatment of ocular neovascular diseases.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:30820226, at figshare; found in “Data availability”

Data availability

All original uncropped western blot images are available on figshare (10.6084/m9.figshare.30820226). Detailed catalog numbers for all reagents and consumables used in this study are listed in Supplementary Table 4. The data supporting the findings of this study are available from the corresponding author upon reasonable request. For data access, please contact.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 5 keywords, 19 MeSH terms, 48 references.

Cite

This paper

Zhang, H., Yu, X., Yang, F., Yu, R., Tan, L., An, J., Wang, H., Cui, Y., Linghu, W., Wang, Y., Wu, J., Zhang, X., & Li, X. (2026). miR-15a-5p outperforms anti-VEGF drug in ocular neovascularization by providing dual anti-angiogenic and neuroprotective effects. Theranostics, 16(14), 8427-8446. https://doi.org/10.7150/thno.134644

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