The evolving landscape of hybrid viral vector architectures: a persisting niche

The development of hybrid viral vectors was historically driven by the need to overcome inherent limitations of individual viral platforms, including restricted payload capacity, narrow tropism, and limited control over genomic persistence. By integrating functional modules from diverse viral and non-viral systems, these chimeric constructs exploit complementary mechanisms to expand therapeutic potential. This review examines the architectural principles underlying hybrid vector design, framing their evolution as a logical extension of viral engineering strategies - such as pseudotyping and genetic chimerization - rather than as a retrospective response to the rise of non-viral delivery platforms. We highlight key structural configurations, including adenoviral, lentiviral, herpes simplex virus (HSV) amplicon, baculoviral, and bacteriophage-derived chimeras, as well as their integration with transposon systems (e.g., Sleeping Beauty) to enable enhanced persistence and increased cargo capacity. In parallel, we analyze the biological and technological trade-offs associated with increased structural complexity, including manufacturing constraints, cumulative immunogenicity, and regulatory challenges. Collectively, hybrid vector systems represent a modular and evolving design paradigm that complements advances in monoplatform vectors and remains a valuable approach for addressing complex therapeutic challenges, for example those requiring expanded capacity, multifunctionality, or combinatorial control of gene delivery outcomes.