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.