Structural and conformational rearrangements of human serum albumin, transferrin, and blood plasma induced by carbosilane dendrimer therapeutic delivery system

Abstract

Abstract Upon intravenous administration, nanoparticles quickly become enveloped by plasma proteins, lipids, and sugars, forming a biomolecular corona that redefines their biological identity and directs systemic distribution. In this study, we examine a third-generation, positively charged, PEGylated carbosilane dendrimer engineered for the delivery of therapeutic siRNA across the blood-brain barrier. Employing a comprehensive array of analytical techniques—including fluorescence quenching assays, circular dichroism spectroscopy, isothermal titration calorimetry, atomic force microscopy, and transmission electron microscopy—we characterize the dendrimer’s binding kinetics and thermodynamics, and its impact on structure of human serum albumin, transferrin and complex environment of plasma. Our findings reveal that the dendrimer induces distinct conformational rearrangements at both tertiary and secondary levels, with thermodynamic analyses indicating that the interactions are predominantly driven by favorable entropy changes and multivalent binding. Furthermore, the dendrimer appears to promote a reorganization of plasma components, potentially leading to aggregation and misfolding reminiscent of fibril formation. Collectively, these findings provide critical insights into the more profound understanding of nanoparticle-protein interactions affecting the biodistribution and hemocompatibility of nanovectors and lay a foundation for further research aimed at safer and more effective therapeutic applications.