PEGylation is a strategy used to improve the efficiency of drug and gene delivery using nanoparticles. By coating nanoparticles with polyethylene glycol (PEG), the surface is protected from aggregation, opsonization, and phagocytosis, thereby prolonging systemic circulation time. This approach has been widely studied and has led to the development of PEGylated nanoparticle formulations for systemic administration, including the FDA-approved drug Doxil. PEGylation has also been utilized to overcome biological barriers in various modes of delivery, such as gastrointestinal and ocular applications. The effectiveness of PEG coatings depends on factors such as PEG molecular weight, surface density, and nanoparticle core properties. PEGylation has been shown to increase the circulation time of nanoparticles, enhance their targeting capabilities, and reduce immunogenicity. However, the use of PEGylated nanoparticles can lead to systemic toxicity, including erythrocyte aggregation and hemolysis. Additionally, the widespread use of PEG has raised concerns about immunogenicity, with the development of PEG-specific antibodies. To address these issues, alternatives to PEGylation, such as poly(amino acids) and poly(glycerol), have been explored. These alternatives have shown promise in improving nanoparticle circulation time and reducing the accelerated blood clearance effect. Overall, PEGylation remains a key strategy for improving nanoparticle-based drug and gene delivery, but ongoing research is needed to address its limitations and develop safer alternatives.PEGylation is a strategy used to improve the efficiency of drug and gene delivery using nanoparticles. By coating nanoparticles with polyethylene glycol (PEG), the surface is protected from aggregation, opsonization, and phagocytosis, thereby prolonging systemic circulation time. This approach has been widely studied and has led to the development of PEGylated nanoparticle formulations for systemic administration, including the FDA-approved drug Doxil. PEGylation has also been utilized to overcome biological barriers in various modes of delivery, such as gastrointestinal and ocular applications. The effectiveness of PEG coatings depends on factors such as PEG molecular weight, surface density, and nanoparticle core properties. PEGylation has been shown to increase the circulation time of nanoparticles, enhance their targeting capabilities, and reduce immunogenicity. However, the use of PEGylated nanoparticles can lead to systemic toxicity, including erythrocyte aggregation and hemolysis. Additionally, the widespread use of PEG has raised concerns about immunogenicity, with the development of PEG-specific antibodies. To address these issues, alternatives to PEGylation, such as poly(amino acids) and poly(glycerol), have been explored. These alternatives have shown promise in improving nanoparticle circulation time and reducing the accelerated blood clearance effect. Overall, PEGylation remains a key strategy for improving nanoparticle-based drug and gene delivery, but ongoing research is needed to address its limitations and develop safer alternatives.