Zheng Liu, Siyuan Song
Viral vectors have transformed gene therapy by enabling efficient and targeted delivery of therapeutics. However, the efficacy and safety of viral vector-based therapies are frequently constrained by host innate immune responses. Sensing of viral capsids, vector genomes, and transgene-derived nucleic acids activates inflammatory and type I interferon signaling, leading to transgene silencing, vector clearance, and immune-mediated loss of transduced cells, particularly at the high vector doses required for clinical efficacy. In contrast, natural viruses have evolved sophisticated mechanisms to evade or modulate these innate immune pathways, enabling sustained gene expression and persistence. This review examines the molecular basis of innate immune sensing of commonly used viral vectors and highlights viral immune evasion strategies as an underexplored resource for therapeutic design. We discuss how repurposing viral immunomodulatory elements-through vector-intrinsic engineering and transient co-delivery-can desensitize innate signaling pathways, thereby enhancing gene transfer while preserving host immune surveillance. Extending these principles beyond viral vectors, we consider their relevance to non-viral platforms, including lipid nanoparticles, polymeric carriers, and exosomes. By reframing viral immune evasion as a therapeutic opportunity rather than a liability, we outline new directions for safer and more effective gene delivery systems.