2D manganese-doped calcium carbonate nanosheets as activable MRI/US imaging Guided enhanced calcium influx for Boosted regulatory cell death

Calcium ion (Ca2+) overload therapy has emerged as a promising approach for regulating mitochondrial functions and inducing immunogenic cell death. However, the limited intramitochondrial Ca2+ levels and immunosuppressive microenvironment significantly hamper its therapeutic efficacy. Herein, we present polyethylene glycol (PEG)-modified 2D manganese-doped calcium carbonate nanosheets (MnCaCP NSs) to improve Ca2+-overload efficacy through increasing the intramitochondrial Ca2+ levels and triggering obvious immunogenic response. The high surface area of MnCaCP NSs facilitates the rapid release of Ca2+ in the mildly acidic tumor microenvironment and quickly elevates intramitochondrial Ca2+ levels in tumor cells. The accompanying released Mn2+ and CO2 disrupted the calcium buffering system of tumor cells by interfering with the oxidative stress and mitochondrial dysfunction, significantly elevating Ca2+ levels and enhancing Ca2+-overload efficacy. We discovered that the increased Ca2+ levels and released Mn2+ activated regulated cell death (RCD) and stimulated the cGAS-STING pathway, transforming tumor tissue from immunosuppressive to immunostimulatory and inhibiting metastasis. Additionally, the tumor micronenvironment-responsive release of Mn2+ and CO2 enables MnCaCP NSs to act as activable magnetic resonance imaging (MRI) and ultrasound (US) contrast agents, allowing for real-time monitoring of therapeutic efficacy. This versatile intelligent nanomedicine integrates controllability, specificity and safety, positioning it as a promising candidate for precision cancer therapy.