Role of Surface Coatings in Preventing Nanoparticle Aggregation Induced by Freeze-Drying

One of the main challenges in nanomedicine is ensuring that nanoparticles maintain their essential physicochemical properties throughout critical stages, such as production, storage, and transportation. In this context, freeze-drying emerges as an attractive solution, enabling the production of nanoparticle-based powders with significantly extended shelf lives. However, despite its advantages, the freeze-drying process imposes stresses during freezing and drying steps, potentially altering nanoparticle properties and promoting undesirable phenomena such as aggregation. Therefore, the addition of protective agents (protectants) is essential to mitigate these detrimental effects. Previous studies have demonstrated that simple carbohydrates and proteins, particularly albumin, effectively preserve the dispersibility of silica nanoparticles during freeze-drying. Building upon this foundation, the present work investigates the protective efficacy of diverse nanoparticle surface coatings including short zwitterions, phosphonates, amines, amine/phosphonate pseudozwitterion and polyethylene glycol (PEG), and their combination with protective agents. Our results show that PEG is the only surface coating capable of preventing freeze-drying-induced aggregation without the need for additional protectants. Moreover, human serum albumin (HSA) consistently outperforms glucose in preserving the colloidal stability of silica nanoparticles with different surface chemistries. By broadening our knowledge of protective strategies, we aim to enhance the stability, dispersibility and overall functionality of nanomedicines, thereby accelerating their successful translation into clinical use.