Protein therapy, wherein therapeutic proteins are delivered to treat disorders, is considered the safest and most direct approach for treating diseases. However, its applications are highly limited by the paucity of efficient strategies for delivering proteins and the rapid clearance of therapeutic proteins in vivo after their administration. Here, we demonstrate a novel strategy that can significantly prolong the circulation time of therapeutic proteins as well as minimize their immunogenicity. This is achieved by encapsulating individual protein molecules with a thin layer of crosslinked phosphorylcholine polymer that resists protein adsorption. Through extensive cellular studies, we demonstrate that the crosslinked phosphorylcholine polymer shell effectively prevents the encapsulated protein from being phagocytosed by macrophages, which play an essential role in the clearance of nanoparticles in vivo. Moreover, the polymer shell prevents the encapsulated protein from being identified by immune cells. As a result, immune responses against the therapeutic protein are effectively suppressed. This work describes a feasible method to prolong the circulation time and reduce the immunogenicity of therapeutic proteins, which may promote the development and application of novel protein therapies in the treatment of diverse diseases.

A complex micelle as a hemoglobin functional model with the biaoactive function of reversible oxygen transfer has been constructed through the hierarchical assembly of the diblock copolymer poly(ethylene glycol)-blockpoly(4-vinylpyridine-co-N-heptyl-4-vinylpyridine) (PEG-b-P(4VP-co-4VPHep)), tetrakis(4-sulfonatophenyl)porphinato iron(II) (Fe(II)TPPS) and β-cyclodextrin (β-CD). The μ-oxo dimer of Fe(II)TPPS was successfully inhibited because the Fe(II)TPPS was included into the cavities of β-CDs through host-guest interaction. Fe(II)TPPS coordinated with pyridine groups functions as the active site to reversibly bind dioxygen. In adition, the host-guest inclusion (β-CD/Fe(II)TPPS) was encapsulated in the hydrophobic core of the complex micelle and tightly fixed by P4VP chains. The hydrophilic PEG blocks stretched in aqueous solution to constitute the shells which stabilize the structure of the complex micelle as well as endow the complex micelle with sufficient blood circulation time. Dioxygen can be bound to the Fe(II)TPPS located in the confined space and excellent reversibility of the binding-release process of dioxygen can be achieved. The quaternary amine N-heptyl-4-vinylpyridine can coerce abundant S₂O₄^2- ions into the core of the complex micelle to facilitate the self-reduction process. Dioxygen adducts (Fe(II)TPPS(O₂)) were effectively protected by the double hydrophobic barriers constructed by the cavity of the cyclodextrin and the core of the complex micelle which enhances the ability to resist nucleophilic molecules. Therefore, the rationally designed amphiphilic structure can work as a promising artificial O₂ carrier. Potentially, the complex micelle can be expected to improve the treatment of diseases linked with hypoxia.