Zwitterionic Poly(ethylene glycol) Nanoparticles Minimize Protein Adsorption and Immunogenicity for Improved Biological Fate.

We report the assembly of poly(ethylene glycol) nanoparticles (PEG NPs) and optimize their surface chemistry to minimize the formation of protein coronas and immunogenicity for improved biodistribution. PEG NPs cross-linked with disulfide bonds are synthesized utilizing zeolitic imidazolate framework-8 NPs as the templates, which are subsequently modified with PEG molecules with different end groups (carboxyl, methoxy, or amino) to vary the surface chemistry. Among the modifications, the amino and residual carboxyl groups form a pair of zwitterionic structures on the surface of PEG NPs, which minimize the adsorption of proteins (e.g., immunoglobulin, complement proteins) and maximize the blood circulation time. The influence of preexisting PEG antibodies in mice on the pharmacokinetics of zwitterionic PEG NPs is negligible, which demonstrates the resistance of anti-PEG antibodies and inhibition of the accelerated blood clearance phenomenon. This research highlights the importance of the surface chemistry of PEGylated NPs in the design of delivery systems and reveals their translational potential for cancer therapy.