Intracellular delivery of His-tagged proteins via a hybrid organic–inorganic nanoparticle

Intracellular delivery of proteins remains challenging. Here, we present a simple and general platform for the efficient loading and delivery of proteins using a methoxy-poly(ethylene glycol)- block -poly(L-phosphotyrosine) (mPEG- b -PpY)-templated calcium phosphate (CaP) hybrid nanoparticle. By doping hybrid CaP nanoparticles with Zn 2+ (CaP-Zn), recombinant proteins bearing a histidine tag can be conveniently loaded by harnessing the His-Zn coordination bond. The resulting protein@CaP-Zn nanoparticles display low toxicity and are tunable, uniform in size, stable under physiological conditions, and degradable in acidic milieu for responsive release. Proteins loaded onto the CaP-Zn nanoparticle can be protected from proteolytic degradation and effectively delivered to intracellular spaces. This work may open up opportunities for protein activity preservation and facilitate the intracellular delivery of recombinant protein therapeutics.