Discovery of Airway-Administered Ionophores for Mn²⁺ to Mitigate Lung Metastasis by Targeting Disseminated Tumor Cell

Activation of the STING pathway is essential for restoring immune surveillance against dormant disseminated tumor cells (DTCs) in the lungs. Inhaled Mn²⁺ has potential as a STING agonist; however, its clinical application is limited by the risk of chronic inflammation and metastasis, primarily due to reactive oxygen species (ROS) generation during inhalation. To address these risks, salvianolic acid B (salB) was identified as an effective ionophore for Mn²⁺, enhancing STING activation while mitigating ROS-induced inflammation. In this study, salB mitigated Mn²⁺-induced ROS levels and enhanced STING signaling, providing a safer, noninflammatory approach to activating immune surveillance in lung DTCs. The salB-Mn²⁺ complexes were encapsulated in human serum albumin nanoparticles (HSA NPs) for inhalation. PET and MRI analyses revealed that intratracheal administration of HSA NP@salB-Mn²⁺ restricted Mn²⁺'s systemic distribution, retaining it primarily in the lungs and minimizing central nervous system accumulation. Subsequent lung immunofluorescence further confirmed that HSA NP@salB-Mn²⁺ effectively targeted lung metastatic lesions. Despite this extended retention in lung tissue, histological analysis showed minimal inflammation in mice treated with HSA NP@salB-Mn²⁺, in contrast to those receiving MnCl₂ or MnO. Consequently, HSA NP@salB-Mn²⁺ demonstrated superior suppression of 4T1 cell lung metastasis in postsurgical mice relative to MnCl₂ or MnO. Mechanistically, salB functions as an agonist, independently activating p-STING, which synergizes with Mn²⁺-induced STING activation to significantly amplify signaling and downstream target engagement. In a postsurgical mouse model, the combination of HSA NP@salB-Mn²⁺ and αPD-1 antibody significantly reduced DTC dormancy and enhanced immune detection, confirming its immunotherapeutic potential. These findings establish salB as a promising inhalable ionophore for Mn²⁺ in DTC treatment, providing three key advantages: prolonged lung retention, reduced inflammation risk, and enhanced STING-activating efficacy.