Drugging “undruggable” neurodegenerative disease targets with small molecules

During the last two decades, an increasing number of reports have pointed out that the immunogenicity of polyethylene glycol (PEG) may trigger accelerated blood clearance (ABC) and hypersensitivity reaction (HSR) to PEGylated nanoparticles, which could make PEG modification counterproductive. These phenomena would be detrimental to the efficacy of the load and even life-threatening to patients. Consequently, further elucidation of the interplay between PEGylated nanoparticles and the blood immune system will be beneficial to developing and applying related formulations. Many groups have worked to unveil the relevance of structural factors, dosing schedule, and other factors to the ABC phenomenon and hypersensitivity reaction. Interestingly, the results of some reports seem to be difficult to interpret or contradict with other reports. In this review, we summarize the physiological mechanisms of PEG-specific immune response. Moreover, we speculate on the potential relationship between the induction phase and the effectuation phase to explain the divergent results in published reports. In addition, the role of nanoparticle-associated factors is discussed based on the classification of the action phase. This review may help researchers to develop PEGylated nanoparticles to avoid unfavorable immune responses based on the underlying mechanism.