Strategies for Evading Cellular Immunity Against Recombinant AAV Vectors in Gene Therapy

Over the past decade, adeno-associated virus (AAV) vectors have emerged as a powerful tool for in vivo gene transfer, owing to their diverse tissue tropisms, predominantly non-integrative property, and superior safety profile compared with other viral vectors. As of December 2025, ten gene therapies based on recombinant AAV (rAAV) vectors have been approved globally, primarily by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA). However, seroprevalence surveys indicate that most individuals carry anti-AAV neutralizing antibodies (NAbs), and nearly 50% of healthy individuals exhibit detectable frequencies of circulating AAV capsid-specific CD8⁺ T cells and/or CD4⁺ T cells. Clinical studies suggest that immune responses mediated by cytotoxic T lymphocytes (CTLs) targeting transduced cells are a key factor limiting the long-term effectiveness of rAAV-mediated gene therapy. Herein, we summarize strategies to evade anti-rAAV cellular immunity, discussing their advantages and limitations in the context of the rAAV transduction process and mechanisms of cellular immune responses. Furthermore, we highlight key challenges in research on rAAV gene therapy immunogenicity, as well as emerging technologies with potential applications in this field.