PEG Alternatives in Liposomal Nanocarriers: Physicochemical Characteristics and Sustainable Process Strategies

ABSTRACT The global trend toward sustainable and intensified bioprocesses is driving innovation in the design and scalable synthesis of liposomal nanocarriers, a cornerstone of modern drug delivery. For decades, these nanosystems have relied exclusively on polyethylene glycol (PEG) for their sustained circulation in vivo, but they are currently challenged by the inherent limitations of PEGylation, including immunogenicity and accelerated blood clearance. The purpose of this review is to critically assess emerging hydrophilic polymers, particularly zwitterionic polymers, as novel and green substitutes for creating “stealth” surfaces on liposomal nanocarriers in long‐term applications. The scalable synthesis, lipid conjugation methods, and intensified processes, such as microfluidics and supercritical fluids, fully aligned with green chemistry principles, are also highlighted in this article. The fundamental emphasis throughout this account, however, is on theoretical models for understanding molecular interactions, particularly polymer‐lipid bilayer interactions, and strategies for suppressing protein corona formation, as these factors are essential for in vivo performance and effectiveness.