Immunogenicity Management Strategies for PEGylated Drug Delivery Systems

The clinical translation and long-term efficacy of PEGylation technology are increasingly jeopardized by its inherent immunogenicity, particularly the induction of anti-PEG antibodies (APAs) and the subsequent accelerated blood clearance (ABC) phenomenon. Furthermore, challenges such as frequent dosing regimens, limited PEG biodegradability, and the increasing prevalence of pre-existing APAs in the general population call for a comprehensive re-evaluation of traditional PEGylation strategies. This review provides a comprehensive and in-depth analysis of recent breakthroughs in addressing PEG-related challenges, ranging from mechanistic understanding of APA generation to actionable clinical interventions. The current core strategies for managing PEG immunogenicity are summarized in this review. To attenuate the immunogenicity, modified PEG or alternatives are developed. To alleviate the immune response, the immune system can be modulated and the clinical dosing regimens are optimized. Their translational potential to overcome the limitations of conventional PEGylation is evaluated. By highlighting emerging solutions and interdisciplinary innovations, we aim to provide a roadmap for the design of next-generation, safer and more effective long-circulating drug delivery platforms that can ultimately benefit a broader patient population.