A primary disadvantage of PEGylation is its tendency to significantly inhibit cellular uptake and endosomal escape, which can lead to a substantial loss of activity for the delivery system.
Understanding the Disadvantage of PEGylation
While PEGylation is widely used to improve the pharmacokinetic properties of therapeutic agents, such as increasing their circulation half-life and reducing immunogenicity, it introduces a critical drawback concerning cellular interaction. The presence of the polyethylene glycol (PEG) polymer on the surface of nanoparticles or drug delivery systems creates a steric hindrance, essentially forming a protective "shield."
This shield, while beneficial for evading immune surveillance and preventing aggregation, also hinders the ability of the therapeutic agent to enter cells (cellular uptake). Furthermore, even if the agent is internalized by a cell, PEGylation can impede its escape from endosomes—small vesicles within the cell that typically trap and degrade foreign materials.
Impact on Efficacy
The inhibition of cellular uptake and endosomal escape directly translates into a significant loss of therapeutic activity. For drugs or gene therapies that require intracellular delivery to exert their effect, this reduced cellular entry and release within the cell can severely compromise their efficacy, rendering the delivery system less effective than intended. This is a crucial consideration, especially for applications like targeted drug delivery or gene therapy, where the active substance needs to reach its intracellular target.
