Advances in synthesis and nanodelivery systems of PEGylated peptide drugs

Peptide drugs, renowned for their exceptional biological activity, high safety profile, and remarkable specificity, have found extensive applications across various domains, including biomedicine, food science, and health product development. However, their clinical utility is hindered by several challenges. Firstly, the pervasive presence of peptidases and inherent excretion mechanisms in the human body leads to rapid degradation and clearance of peptides, resulting in poor stability and a short plasma half-life. Secondly, the oral administration of peptide drugs is compromised by the digestive enzymes in the oral cavity, which readily break the amide bonds, and by the intestinal mucosal barrier, which impedes the absorption of highly polar and larger molecular weight peptides. Thirdly, the polarity, hydrophilicity, and charge of peptide drugs pose significant barriers to their ability to cross cell membranes, physiological barriers, and the blood-brain barrier, thereby limiting their efficacy and practical applications. To address these challenges, PEGylation technology, a chemical modification approach involving the covalent attachment of polyethylene glycol (PEG) chains to peptide molecules, has emerged as a highly effective strategy. This modification confers several critical advantages, including enhanced water solubility due to the hydrophilic nature of PEG, which shields the hydrophobic regions of the peptide and prevents aggregation. Moreover, the steric hindrance provided by PEG chains offers protection against enzymatic degradation and chemical modification, thereby enhancing the stability of the peptide. These factors, combined with reduced renal clearance and avoidance of recognition by the reticuloendothelial system, collectively contribute to an extended half-life and improved pharmacokinetic properties, making PEGylated peptides more suitable for therapeutic applications. PEGylated peptides also exhibit unique self-assembly capabilities, forming various nanostructures such as micelles, fibers, vesicles, and hydrogels, which serve as versatile platforms for drug delivery. This review delves into the development of responsive PEGylated peptide nanosystems that are triggered by specific stimuli like pH, ROS, light, or enzymes, enabling controlled drug release at the target site and minimizing off-target effects. These nanosystems can encapsulate both hydrophobic and hydrophilic drugs, enhancing their solubility and stability, while the stealth properties conferred by PEGylation reduce immune recognition. Despite the numerous advantages of PEGylation, certain challenges persist. The synthesis of PEGylated peptides is complex and requires meticulous control over reaction conditions to achieve the desired modifications. Additionally, the selection of PEG length and structure significantly impacts the properties of the resulting PEGylated peptide, necessitating careful optimization for each specific application. Future research is poised to focus on the development of efficient PEGylation drug delivery systems, aiming to further enhance therapeutic efficacy, improve safety profiles, and achieve precise drug targeting while minimizing adverse effects. This comprehensive review systematically examines the historical progression of PEGylation peptide research, summarizes the publicly available PEGylated peptide/protein drugs, outlines representative chemical and enzyme-mediated synthesis methods, and highlights the latest developments. It also explores the potential and challenges of PEGylation in peptide drug functional modification and nano-delivery systems, providing valuable theoretical insights to inform the rational design and development of next-generation peptide-based pharmaceuticals.