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Reduction of choroidal neovascularization via cleavable VEGF antibodies conjugated to exosomes derived from regulatory T cells

Abstract

Choroidal neovascularization induced by age-related macular degeneration and retinal neovascularization induced by diabetic retinopathy—two leading causes of blindness—are often treated using antibodies targeting vascular endothelial growth factor (VEGF). Here we report a strong association between inflammation and high VEGF expression in aqueous humour samples from patients with choroidal or retinal neovascularization, and show that intravitreally injected exosomes derived from regulatory T cells and conjugated with an anti-VEGF antibody via a peptide linker that is cleavable by matrix metalloproteinases markedly suppressed ocular neovascularization in mouse and non-human primate models of choroidal neovascularization. The engineered exosomes, which selectively accumulate in the neovascularization lesions, could be adapted for other combination therapies of therapeutic antibodies and anti-inflammatory cargo.

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Fig. 1: Co-morbidity of VEGF and inflammation in patients with CNV and histological analysis of intraocular inflammation in a laser-induced CNV mouse model.
Fig. 2: Preparation and characterization of rEXS–cL–aV.
Fig. 3: Controlled spatiotemporal release and dual anti-VEGF and anti-inflammation activity in CECs and M1 macrophages co-incubated in the Transwell assay.
Fig. 4: Intraocular retention, CNV lesion targeting, and spatiotemporally controlled release ability of rEXS–cL–aV in a laser-induced CNV mouse model.
Fig. 5: Therapeutic effects and safety of rEXS–cL–aV in a laser-induced CNV mouse model.
Fig. 6: Therapeutic effects and safety of rEXS–cL–aV in a laser-induced CNV non-human primate model.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data for the figures are available as Supplementary Information and also at figshare: https://figshare.com/articles/dataset/Source_Data_xlsx/14401208. The RNA-sequencing data are available at the NCBI BioProject under accession PRJNA721185. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82070948, U2001224), the Beijing Chaoyang 1351 talent training programme (CYXX-2017-21) and the Scientific Research Program of Beijing Municipal Commission of Education (KM202010025020).

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W.W., Y. Tao and D.Y. conceived and designed the study. Y. Tian, F.Z., Y.Q., S.W., F.L., J.Z. and C.P. performed the experiments: Y. Tao and Y. Tian collected and analysed the clinical samples; F.Z. and F.L. helped with nanodrug preparation and experimental assays; and Y.Q. and C.P. assisted with the cynomolgus monkeys model experiment. S.W. and J.Z. facilitated the data and file processing. All authors discussed the results and commented on the manuscript. D.Y., W.W., Y. Tian and F.Z. wrote the manuscript, and W.W., Y. Tao and D.Y. revised and edited the manuscript.

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Correspondence to Yong Tao, Di Yu or Wei Wei.

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Peer review information Nature Biomedical Engineering thanks Nicholas Agard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Tian, Y., Zhang, F., Qiu, Y. et al. Reduction of choroidal neovascularization via cleavable VEGF antibodies conjugated to exosomes derived from regulatory T cells. Nat Biomed Eng 5, 968–982 (2021). https://doi.org/10.1038/s41551-021-00764-3

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