Non-Viral Gene Delivery Systems: Current Advances and Therapeutic Applications

Gene therapy holds immense potential for treating genetic disorders, malignancies, and infectious diseases through the targeted introduction, silencing, or precise editing of therapeutic genes. Although viral vectors exhibit exceptionally high gene transfection efficiency, their clinical application faces significant challenges, including robust immunogenicity, the insertional mutagenesis risks, complex and costly manufacturing processes hindering large-scale manufacturing, limited gene cargo capacity, and poor packaging efficiency for large genes. In contrast, nonviral vectors—such as lipid nanoparticles (LNPs), cationic polymers, and inorganic nanoparticles, offer numerous advantages, including superior safety profiles, the scalability for manufacturing, structural and functional reconfigurability in accommodating various sizes cargo. Consequently, these nonviral delivery platforms have emerged as promising alternatives in DNA/mRNA/siRNA delivery. This review systematically summarizes recent progress in nonviral gene delivery systems, highlighting their therapeutic potential and current challenges. We systematically investigate the cellular internalization mechanisms and intracellular trafficking pathways of gene-loaded nanoparticles, and explore their diverse applications in gene therapy. Furthermore, this review systematically summarizes recent examples of clinically approved nonviral vector-based gene therapies including vaccine development, genetic disease treatment, and cancer therapy. Finally, we highlight the current challenges and future perspectives for the clinical translation of the nonviral delivery vectors.