Structure-centered design of lipid-based nanocarriers to overcome biological barriers

As technology has evolved in response to pressing human challenges, drug delivery systems (DDSs) have also evolved to overcome complex biological barriers. Particularly, the continuous development of therapeutic strategies has enabled the integration of nanotechnology, leading to the emergence of diverse nanoscale DDSs. Concerns about the potential toxicity of nanomedicines diverted attention to lipid-based nanocarriers (LBNs), regarded as safer and more biocompatible platforms. In this review, the structural evolution of LBNs is categorized into three stages according to the increasing functional complexity required to address biological barriers, providing a framework to understand how designs advanced with physiological demands. This trajectory encompasses emulsions and LBNs, with each stage advanced by strategies such as lipid composition tuning, surface functionalization, biomimetic construction, and hybridization with other platforms. Over a few decades, this transition has described that the progression of LBNs reflects not merely chronological advances but a stepwise evolution of structural adaptations shaped by biological barriers. This analytical perspective is presented through a comprehensive discussion of the structural strategies utilized in recent LBN research. Consequently, structural evolution provides a foundation for refining design approaches in drug delivery and achieving improved therapeutic outcomes.