Introducing Sulfur Ylides as Charge-Neutral Termini for Mitigating Poly(ethylene glycol) Antigenicity in Nanomedicine

The widespread use of polyethylene glycol (PEG) in biomedical applications has led to the emergence of anti-PEG antibodies, which accelerate systemic clearance and undermine the performance of PEGylated systems, including those of nanomedicines. Antibody recognition often involves the hydrophobic PEG terminus, highlighting the need for alternative end-functionalization strategies that enhance hydrophilicity while maintaining stealth properties. Here, we introduce a novel PEGylation concept using sulfur ylides bearing tri- and pentapeptides as terminal modifications. These ylide-PEG (yPEG) conjugates were integrated into polymeric nanoparticles as a model system, demonstrating that ylide functionalization maintains key physicochemical properties, such as ζ-potential and antifouling behavior. Crucially, antibody binding assays with monoclonal IgM and IgG anti-PEG antibodies revealed that the ylide terminus significantly reduces recognition by both main chain- and terminus-specific anti-PEG antibodies. Experiments with polyclonal anti-PEG antibodies from mPEG-immunized mice suggest that increasing the chemical complexity of the PEG terminus with a strongly hydrophilic yet overall charge-neutral group effectively prevents antigenicity from extending to the terminus, ultimately reducing PEG-specific recognition. This modular and scalable strategy of yPEGs offers a new paradigm for engineering stealth-functionalized polymers with broad implications for nanomedicine, biomaterials, and surface coatings.