Calcium citrate nanoparticles as a new frontier in metabolic acidosis treatment

Metabolic acidosis often coexists with systemic diseases, contributing to cellular dysfunction through mechanisms such as protein degradation, bone loss, renal impairment, inflammation, oxidative stress, and apoptosis. Standard alkalinizing agents, such as sodium bicarbonate and sodium citrate, can cause gastrointestinal side effects, limiting their long-term use. To address this, we developed calcium citrate nanoparticles (CN) and calcium citrate-loaded calcium carbonate nanoparticles (CCN) for potential adjuvant therapies or as drug carriers. CN and CCN exhibited particle sizes of 50 to 70 nm and 60 to 80 nm, with zeta potentials of -16.1 and -13.0 mV, and citrate content of 31% and 25%, respectively. Both nanoparticles showed efficient cellular uptake in normal and acidic environments with minimal cytotoxicity at 1 mg ml^-1. Although CN had only a slight alkalinizing effect in vitro, intracellular and extracellular bicarbonate levels did not differ significantly between treatment groups after 24 hours. In particular, acidosis-induced oxidative stress was significantly attenuated by CN and CCN, outperforming sodium citrate. Flow cytometry further demonstrated superior protection by CN and CCN against acidosis-induced cell injury. These findings support the potential of calcium citrate nanoparticles in safe and effective adjuvant therapies for metabolic acidosis, offering enhanced antioxidant protection and reduced cellular damage compared to those with conventional treatments.