Background and purpose: Gene therapy has emerged as a transformative strategy for treating genetic and acquired disorders, but its clinical success relies heavily on the development of safe, efficient, and target-specific delivery vectors. Experimental approach: The paper systematically analysed published evidence on liposome composition, physicochemical behaviour, targeting strategies, and their applications in delivering diverse nucleic acids, with emphasis on the structure-function relationships of lipid components and the impact of biophysical parameters on transfection efficiency. Key results: Current findings demonstrate that the molecular architecture of cationic, neutral, and anionic lipids, particularly variations in head groups, linkers, and hydrophobic tails, strongly dictates liposome stability, cellular uptake, and cargo release. Biophysical attributes such as vesicle size, zeta potential, membrane fluidity, fusion capacity, and PEGylation were identified as major determinants of in vivo fate. Active targeting through ligands, including antibodies, peptides, folate, and aptamers, enhances cell-specific delivery, while combinatorial approaches with physical enhancement techniques such as sonoporation and electroporation further improve nucleic acid transport. Conclusion: By integrating structural, functional, and application-based insights, this review highlights key design principles for optimizing next-generation liposomal vectors, although challenges remain in achieving consistent in vivo performance and clinical translation. The work advances the field by offering a unified framework to guide rational engineering of liposomal platforms for gene therapy.
