# MSC‐Derived Exosomal lnc‐AGT‐3: A Novel Anti‐Angiogenic Target in Age‐Related Macular Degeneration Through p53 Signaling Pathway

## TL;DR

This study identifies a long non-coding RNA, lnc-AGT-3, in exosomes from stem cells that can reduce harmful blood vessel growth in a common eye disease by boosting the p53 pathway.

## Contribution

The study reveals lnc-AGT-3 as a novel anti-angiogenic target in nAMD through its regulation of the p53 signaling pathway.

## Key findings

- lnc-AGT-3 expression is reduced in nAMD patients and CNV models.
- Overexpression of lnc-AGT-3 inhibits pathological angiogenesis in vitro and in vivo.
- lnc-AGT-3 stabilizes p53 by blocking its ubiquitination and interacts with hnRNP K.

## Abstract

Neovascular age‐related macular degeneration (nAMD) is a major cause of irreversible vision impairment in elderly populations, characterized by pathological angiogenesis beneath the macula. Although anti‐VEGF therapies have demonstrated clinical effectiveness, significant challenges including drug resistance and the need for frequent intravitreal injections persist. As natural nanovesicles, exosomes derived from mesenchymal stem cell (MSC) can mediate intercellular communication, making them an attractive alternative for modulating cellular processes. This study explored the anti‐angiogenic effects of MSC‐derived exosomes in nAMD, with particular emphasis on the role of a specific exosomal lncRNA lnc‐AGT‐3. Our results showed that lnc‐AGT‐3 expression was reduced in both nAMD patients and choroidal neovascularization (CNV) models, and its overexpression effectively inhibited pathological angiogenesis in vitro and in vivo. Mechanistically, lnc‐AGT‐3 enhanced the p53 signaling pathway by blocking the ubiquitination and degradation of p53 and ultimately inhibited neovascularization, a process potentially linked to its direct interaction with heterogeneous nuclear ribonucleoprotein K (hnRNP K). Our findings position MSC‐derived exosomes enriched with lnc‐AGT‐3 as an innovative therapeutic paradigm for nAMD, acting through p53 pathway modulation to potentially overcome current treatment limitations.

MSC‐derived exosomes deliver lnc‐AGT‐3 to vascular endothelial cells, where it binds hnRNP K in the nucleus. This interaction inhibits p53 ubiquitination, enhancing p53 stabilization and transcriptional activation of anti‐angiogenic targets TSP1. Consequently, p53‐mediated signaling is potentiated, effectively suppressing choroidal neovascularization in AMD.