Abstract: Non-Small Cell Lung Cancer (NSCLC), the predominant lung cancer subtype, causes high morbidity and mortality due to its complex pathogenesis, late diagnosis, and multidrug resistance, which limit effective treatment. Physiological barriers, nonspecific drug distribution, and systemic toxicity of the current traditional therapies and current nanocarrier systems have limited their success. The next-generation drug delivery system, engineered liposomes, has emerged to overcome these limitations to enhance the site-specific delivery and improve the therapeutic outcomes. This review examines the engineering and utilization of engineered liposomes to address NSCLC therapy. It begins with an overview of NSCLC and the biological and physiological obstacles associated with its treatment. Limitations of current nano-formulations highlight the rationale for engineered liposomes, which offer improved permeability, targeted delivery, controlled release, and co-delivery of drugs and genetic materials. Special emphasis is placed on their design features, including surface modifications, ligand conjugation, and stimuli-responsive mechanisms that improve tumor targeting and cellular uptake. Mechanistic insights into how engineered liposomes interact with tumor cells, bypass efflux pumps, and facilitate intracellular delivery are presented. Their use in chemotherapy, combination therapy, RNA/gene therapy, and theranostic monitoring is demonstrated in current in vitro, in vivo, and clinical studies. This review also addresses regulatory and safety considerations and concludes with future perspectives, including the potential translation of these systems to other malignancies such as glioblastoma.
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