Liposomal nanocarriers are clinically established platforms for targeted drug delivery due to their biocompatibility and ability to encapsulate both hydrophilic and hydrophobic agents. However, conventional single-drug liposomes are limited by suboptimal efficacy, systemic toxicity, and multidrug resistance. Dual-drug-loaded liposomes (DDLs) address these limitations by enabling co-delivery of synergistic agents within a single nanocarrier. This review provides an integrated analysis of DDL systems, focusing on formulation design, drug loading strategies, and key physicochemical parameters governing encapsulation efficiency and controlled release. Mechanistic insights into therapeutic enhancement are highlighted, including modulation of efflux transporters, reversal of epithelial–mesenchymal transition, and synchronized intracellular delivery. The impact of ligand-mediated functionalization on tumor targeting and cellular uptake is also critically evaluated. Unlike existing reviews, this work provides a unified framework integrating formulation design, mechanistic insights into drug synergy, and translational challenges specific to DDLs, addressing a critical gap in the existing literature. Preclinical and clinical evidence, including approved formulations such as Vyxeos, is discussed. Remaining barriers include scale-up, reproducibility, immune interactions, and regulatory complexity. Future directions emphasize personalized and stimulus-responsive nanomedicine for improved cancer therapy.
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