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Short in vivo circulation is a major hindrance to the widespread adoption of protein therapeutics. Protein nanocapsules generated by encapsulating proteins with a thin layer of phosphorylcholine-based polymer via a two-step encapsulation process exhibited significantly prolonged plasma half-life. Furthermore, by constructing nanocapsules with similar sizes but different surface charges and chemistry, we demonstrated a generic strategy for prolonging the plasma half-life of therapeutic proteins. In an in vitro experiment, four types of bovine serum albumin (BSA) nanocapsules were incubated with fetal bovine serum (FBS) in phosphate buffer saline (PBS); the cell uptake by HeLa cells was monitored to systematically evaluate the characteristics of the surface chemistry during circulation. Single positron emission tomography–computed tomography (SPECT) was employed to allow real-time observation of the BSA nanoparticle distribution in vivo, as well as quantification of the plasma concentration after intravenous administration. This study offers a practical method for translating a broad range of proteins for clinical use.
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