Structure-driven design of albumin-based drug delivery systems

Albumin, the most abundant plasma protein in circulation, has emerged as a versatile platform for drug delivery owing to its excellent biocompatibility, long half-life, and remarkable structural adaptability. In the past decades, many review and research articles regarding albumin-based drug delivery systems have been published, and there is a growing need to re-examine this body of literature from a new perspective. In this review, we adopt a structure-driven perspective to comprehensively analyze the fundamental mechanisms of albumin accommodating diverse therapeutic molecules. We detail how different drug loading approaches-namely physical adsorption, covalent conjugation, protein corona formation, and refolding-assisted encapsulation-are intrinsically linked to the hierarchical architecture of albumin, including its α-helical domains, hydrophobic subdomains, and dynamic conformational plasticity. By elucidating the chemical principles and structural determinants underlying each loading strategy, we aim to provide a unified framework that can inform the rational design of next-generation albumin-based drug delivery systems with enhanced loading efficiency, stability, and controlled release profiles. This structure-focused understanding may offer new insights into optimizing albumin carriers for improved clinical translation.