Sodium Chloride Nanoparticles Potentiate Radiation Therapy by Disrupting Osmolarity Balance and Enhancing Antitumor Immunity

Abstract

This study investigates sodium chloride nanoparticles (SCNPs) as radiosensitizers. In contrast to conventional radiosensitizers that rely on high-Z effects or DNA-targeted mechanisms, SCNPs potentiate radiation-induced cellular damage by perturbing ion homeostasis. Importantly, SCNPs by elevating intracellular sodium levels reverse the sodium/calcium exchanger (NCX), leading to calcium influx. This calcium surge not only amplifies radiation-induced cancer cell death but also activates the cGAS-STING pathway, leading to the production of type I interferons. In syngeneic head and neck cancer models, SCNPs significantly improve tumor control and long-term survival in combination with radiation, without inducing detectable toxicity. Mechanistic studies reveal that these therapeutic benefits are largely immune-mediated, demonstrated by enhanced dendritic cell maturation and increased tumor infiltration of T cells. Overall, SCNPs are poised to overcome the limitations of conventional radiosensitizers, such as systemic toxicity and reduced efficacy with megavoltage beams, and offer a mechanistically distinct approach with significant translational potential.