A versatile pH-responsive platform for intracellular protein delivery using calcium phosphate nanoparticles

Intracellular protein delivery has great biomedical applications; the safe and efficient delivery vectors are crucial for achieving this goal. Here we report a platform for efficient protein delivery using calcium phosphate (CaP) nanoparticles. The well-dispersed and highly-stable nanoparticles (∼100 nm) are prepared with the protein loading capacity of up to 29%. The nanoparticles are stable under serum conditions; however, after being internalized into cells, the particles quickly release protein in the weak acidic endosomes/lysosomes. The decomposition of CaP promotes the endo-lysosomal escape of proteins released from nanoparticles. The protein/CaP conjugates were prepared under mild conditions (aqueous solution, room temperature); hence the protein released from nanoparticles retained its folding and function. In addition, all materials used for the preparation are highly biocompatible. This method has been applied for the loading of three model proteins, BSA, GFP and KillerRed; similar loading properties were observed on these proteins. Therefore, this work offers a general approach for intracellular protein delivery, which could be applicable for therapeutic proteins.