Toward Safe and Effective Gene Therapy: Non-Viral Nanostructured Delivery Systems

Gene therapy has emerged as a transformative strategy for treating a wide range of genetic and acquired disorders. Despite its potential, clinical translation is hindered by the limitations of viral vectors, including immunogenicity, insertional mutagenesis, limited cargo capacity, and production challenges. Consequently, non-viral gene delivery systems have gained increasing attention as safer, more versatile alternatives. These platforms, including lipid-based nanoparticles, polymers, dendrimers, inorganic nanocarriers, and hybrid systems, offer customizable physicochemical properties, scalable manufacturing, and reduced risk of adverse immune responses. This review systematically expresses recent advances in non-viral vectors, focusing on the key parameters that influence cellular uptake, endosomal escape, nuclear localization, and overall transfection efficiency in various disease, especially cancers. Additionally, we evaluate recent preclinical and clinical studies, highlighting promising translational outcomes and therapeutic applications. By comparing different non-viral strategies and discussing their mechanistic underpinnings, this review underscores the potential of non-viral vectors to overcome the inherent limitations of viral delivery and to drive the development of next-generation gene therapy approaches that are safer, more adaptable, and clinically relevant.