Imidazole-Based Liposomes: Emerging pH-Sensitive Drug Delivery Tools

pH-sensitive liposomes represent a promising platform for targeted drug delivery, with imidazole-based lipids offering unique advantages for tumor-specific release and enhanced endosomal escape. This pH-responsiveness facilitates cellular uptake through electrostatic interactions and improves intracellular delivery, primarily via the proton sponge effect and membrane fusion mechanisms. This article provides a comprehensive overview of imidazole-modified liposomes, detailing their pH-responsiveness mechanisms, diverse formulations, and highlighting current gaps and future research directions within the field. Special attention is given to the characteristics, advantages, and applications of key structures, including imidazole-lipid compounds, imidazole-cholesterol conjugates, and histidine-bearing polymers. The incorporation of imidazole has been shown to optimize drug release profiles, enhance intracellular delivery, and improve cytotoxicity toward cancer cells, while maintaining a favorable safety profile under physiological conditions comparable to conventional liposomes. Recent advancements highlight the impact of structural modifications, such as carbon chain length optimization, conjugated moieties, and polymer architecture, on modulating liposome stability, drug release kinetics, and targeting efficiency. Despite these notable advancements, significant challenges persist, including the critical balance between carrier stability and pH sensitivity, immune clearance, endosomal entrapment, and the complexities associated with large-scale synthesis.