Complement Activation: A Potential Threat on the Safety of Poly(ethylene glycol)-Coated Nanomedicines

In this issue of ACS Nano, Chen et al. provide in vitro and in vivo evidence for monoclonal anti-poly(ethylene glycol) (anti-PEG) antibody-triggered, complement terminal complex-mediated damage to PEGylated liposomal doxorubicin, entailing the release of the encapsulated drug from the vesicles. These results reveal a new dimension of the potential damage of anti-PEG antibody-mediated complement activation on PEGylated nanomedicines in addition to previous observations on infusion hypersensitivity reactions and the accelerated blood clearance effect. The possibility of a destructive attack of the complement system on the liposome drug carrier may have safety implications in patients displaying high levels of preformed anti-PEG antibodies. In this Perspective, we summarize the experimental and clinical data highlighting the relationships among the above adverse immune phenomena and the options available for reducing the risk of immune damage caused by PEGylated nanomedicines.