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.