The amazing AAV capsids: Into the structure-verse

Over the past ∼25 years, structural studies of adeno-associated virus (AAV) capsids have greatly aided our understanding of the biology of these single-stranded DNA viruses and provided insights into their utilization as gene therapy vectors for the treatment of various human diseases. Recent advances in cryo-electron microscopy have yielded a library of currently ∼150 high-resolution AAV capsid structures, with more than 50% determined in the last 5 years alone. Comparative analyses of capsids from primate and nonprimate origins have revealed both conserved architectural elements, such as the canonical jelly-roll fold, and critical surface variations that affect receptor interaction, antibody recognition, and intracellular trafficking. These structures, as well as those in complex with glycan and proteinaceous receptors, purification agents, and antibodies, have been instrumental in rational capsid engineering, guiding the design of new variants with enhanced transduction efficiency, tissue specificity, and reduced detection by pre-existing neutralizing antibodies. This review summarizes the available AAV capsid structures to date, highlighting landmark discoveries over the years, and offers perspectives on how structural biology will continue to drive innovation in AAV gene therapy.