Advances in stabilizing lipid-based nanoparticles: The central role of lyophilization

Lipid-based nanoparticles (L-bNPs) have become a key platform in nanomedicine, enabling advances in drug delivery, gene therapy, and vaccine development. However, their widespread clinical application remains limited by their poor long-term stability, especially when stored in aqueous media. This review provides a comprehensive overview of long-term storage strategies for L-bNPs, with a particular focus on lyophilization (freeze-drying), which has emerged as the most widely adopted and effective stabilization method in the biopharmaceutical industry. The review begins with a classification of lipid-based nanoparticles and their medical applications, followed by an analysis of key storage challenges and a detailed exploration of freeze-drying processes, including critical parameters such as cryoprotectant selection, vial type, and the lipid composition of the formulation. Additionally, novel approaches such as spin freeze-drying are discussed for their potential to optimize solvent distribution and product morphology. Other long-term storage methods-including cryopreservation and atomization-based drying techniques such as spray-drying and supercritical fluid drying (SCFD)-are also examined for their potential benefits. Spray congealing, though still under development for L-bNPs, is highlighted for its promising performance in related lipid-based systems. While lyophilization remains the gold standard, the choice of method must be tailored to the physicochemical properties of the L-bNPs and their intended therapeutic use. Future perspectives highlight the need for more standardized protocols and advanced analytical tools to ensure stability and effectiveness across storage and transport conditions.