Pyrophosphate as a Phosphate Donor for the Design of Stable and pH-Responsive Calcium Nanoparticles for Biomacromolecule Encapsulation

Calcium phosphate-based nanoparticles (CaPNPs) are widely utilized for biomedical applications due to their biocompatibility and encapsulation properties. The pH-responsive nature of phosphate enables the biodegradation of CaPNPs under acidic conditions. However, they often suffer from gradual dissolution in aqueous conditions, particularly when the structure is highly amorphous. Herein, we report that pyrophosphate serves as a phosphate donor to construct nanoparticles with enhanced stability. Pyrophosphate ions possess a higher anionic valence compared to phosphate ions, resulting in strengthened electrostatic interactions with calcium ions. Interestingly, the developed calcium pyrophosphate-based nanoparticles (CaPPiNPs) achieved structural crystallinity, whereas CaPNPs remained amorphous, despite the preparation without thermal treatment; consequently, CaPPiNPs exhibited superior dilution resistance and enhanced stability under physiological conditions compared to CaPNPs. CaPPiNPs also improved encapsulation capacity for biomacromolecules while achieving pH-responsive degradation for the payload release, ultimately suggesting the potential of pyrophosphate as a key component to construct biodegradable nanoparticles capable of encapsulating foreign substances.