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

Abstract

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.