# Advances in endothelial cell targeting by AAV vectors

## TL;DR

This paper reviews recent strategies to improve gene delivery to endothelial cells using modified AAV vectors, which could advance therapies for vascular and inflammatory diseases.

## Contribution

The paper highlights novel approaches like capsid engineering and polymer coatings to redirect AAV vectors toward endothelial cells.

## Key findings

- AAV4 serotype shows unique endothelial tropism due to its recognition of O-linked sialic acids.
- EC-binding peptides and genetic modifications can enhance endothelial targeting while reducing off-target effects.
- Polymer coatings improve receptor-specific targeting of endothelial cells and reduce immune recognition.

## Abstract

Adeno-associated virus (AAV) vectors have become a cornerstone of in vivo gene delivery. However, although the endothelium is the first cellular interface encountered after systemic delivery, native AAV serotypes exhibit poor endothelial transduction, favoring hepatocytes, muscle cells and, neurons instead. This limitation represents a major barrier to gene therapies targeting cardiovascular, neurovascular, and inflammatory diseases. This review summarizes recent advances in redirecting AAV tropism toward endothelial cells (ECs) through genetic capsid engineering, peptide display, and non-genetic surface modification. We highlight the previously underrecognized endothelial tropism of the AAV4 serotype, attributed to its unique recognition of O-linked sialic acids. We also describe multiple approaches to capsid retargeting, including the incorporation of EC-binding peptides that enable cell entry into specific vascular beds, as well as genetic engineering strategies that reduce heparan sulfate proteoglycan (HSPG) binding and hepatocyte transduction while enhancing intracellular trafficking in ECs. In addition, we discuss polymer-coating approaches that allow receptor-specific targeting of ECs with reduced recognition by immune cells. Together, these strategies represent promising avenues for enhancing vascular tropism and transduction efficiency of modified AAVs, moving the field closer to precise vascular gene therapies.