Advances in endothelial cell targeting by AAV vectors

Adeno-associated virus (AAV) vectors have become a cornerstone of <i>in vivo</i> 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.