Recent advancements in improving cross-species applicability of bioengineered AAV capsids

Adeno-associated virus (AAV) is widely accepted as a delivery vector for in vivo gene therapy due to its relatively low immunogenicity, minimal toxicity, sustained efficacy, and broad tropism. However, its unpredictable cross-species applicability remains a troublesome hurdle for broader clinical applications. Thus, designing novel AAV capsids with enhanced cross-species applicability is urgently needed. In this review, we present AAV bioengineering methods, including rational design, directed evolution, and artificial intelligence–based design, with the goal of creating novel AAV variants that are translatable to humans. Using representative examples, we also evaluate how each method addresses key species-dependent barriers—receptor usage, intracellular trafficking, immune recognition, and toxicity—that critically determine cross-species translatability.