From LNPs to hybrid nanocarriers: development, challenges and redesign of non-viral gene delivery.

Gene therapy has become a cornerstone of precision medicine, offering potential solutions for a wide spectrum of disorders at the molecular origin. However, the clinical performance of gene therapeutics is critically determined by the efficiency and safety of delivery vectors. Though viral vectors are widely used in gene therapy because of their high delivery efficiency, the safety concern remains a major limitation. In contrast, non-viral vectors have attracted increasing attention owing to their favorable safety profiles, structural tunability, larger cargo capacity, and scalable production. In this review, we examine five major classes of non-viral gene delivery vectors, including Lipid Nanoparticles (LNP), polyplexes, lipoplexes, and exosomes, together with their corresponding hybrid systems. For each platform, we summarize structural features, delivery mechanisms, therapeutic applications, and translational challenges, and further discuss how hybrid architectures integrate complementary properties from different vectors to overcome limitations inherent to single-component systems. By organizing these delivery strategies within a unified structure-function-application framework, this review provides an integrated perspective on non-viral vector design and highlights hybrid systems as an increasingly important direction for the optimization of clinically relevant gene delivery platforms.