The Art of PEGylation: "From Simple Polymer to Sophisticated Drug Delivery System"

The development of effective drug delivery systems is a major challenge in cancer therapy, gene therapy, and infectious disease treatment because of its low bioavailability, rapid clearance, and toxicity towards non-targeted healthy tissues. This review discusses how PEGylation, the covalent attachment of poly(ethylene glycol) (PEG), enhances the pharmacokinetic profiles of the drug-containing nanosystems through the "stealth effect" that avoids immune system detection and improves circulation times in different nano-delivery systems. The review provides an overview of the synthetic methods of PEG derivatives, their conjugation with nanoparticles, proteins, and drugs, and their characterization using modern analytical tools. The paper explores various PEGylation strategies, including covalent conjugation and self-assembly, and discusses the influence of PEG chain length, density, and conformation on drug delivery efficiency. Despite its advantages, there are several challenges associated with PEGylation such as the immunogenicity of anti-PEG responses, the potential for accelerated clearance of PEGylated drugs, reduced therapeutic efficacy, and the possibility of allergic reactions. Consequently, the balance between the benefits of PEGylation and its immunogenic risks remains a critical area of investigation.