The colloidal stability of albumin-based drug delivery systems has a profound effect on tumoricidal activity

Human serum albumin (HSA) has attracted significant attention in drug delivery since the approval of Abraxane in 2005. Abraxane is a nanoparticle albumin-bound paclitaxel (nab-PTX) formulation. Although HSA offers advantages such as prolonged circulation time (half-life ~19 days) and intrinsic hydrophobic pockets, the translation of other HSA-based nanomedicines remains limited. In fact, the significant differences between native and pharmaceutical HSA in protein structure and biological interactions could hinder their translational use in drug delivery. In this study, we demonstrate that pharmaceutical HSA (α-helix = 17%) is structurally denatured compared with native HSA (α-helix = 68%), leading to rapid clearance (ζ = −13.7 mV), leading to aggregation, and low colloidal stability, resulting in premature drug release upon dilution (ζ = −27.4 mV) and improved colloidal stability to reduce the premature release of encapsulated PTX upon dilution (p Created with Biorender.com.