AUTHOR=Cichon Milena , Jozkowicz Alicja , Grochot-Przeczek Anna 
  
TITLE=Advances in endothelial cell targeting by AAV vectors
  
JOURNAL=Acta Biochimica Polonica
  
VOLUME=Volume 73 - 2026
  
YEAR=2026
  
URL=https://www.frontierspartnerships.org/journals/acta-biochimica-polonica/articles/10.3389/abp.2026.15740
  
DOI=10.3389/abp.2026.15740
  
ISSN=1734-154X
  
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.