Oligonucleotide is emerging as a novel class of therapeutics due to its high specificity, and ability to manage the incorrigible diseases with targeted action. The expedited growth evident from past few decades unveils the potentiality of the oligonucleotide as the future medicine. Various studies based on the vector-based system have shown the superiority of the lipid over other non-viral vectors. The lipid-based systems are most often exploited for the development of safe and efficient gene delivery systems. The factors influencing the structure, stability, internalization, and transfection of the lipoplex required for effective lipoplex delivery system are being explored. Furthermore, safety considerations and the status of lipoplex clinical trials are also addressed. The need of more scalable methods, which can be applied at industrial level, is identified and exploited. The aim is to manufacture products with long-term shelf life to support clinical trials and their subsequent market use. The design of lipoplexes leads to efficient entrapment of nucleic acid with enhanced in-vitro and in-vivo milieu stability, facilitating uptake and cellular targeting. The increasing number of entry of lipoplex-based gene therapy in the clinical trials shows the potential of lipoplex as a well-characterized system with consistent quality and reliable performance. The concomitant development of novel lipids, enhanced understanding of the uptake mechanism and formulation design characteristics have increased lipoplex-based oligonucleotide delivery system access to and success in the clinical trials and regulatory nod.