X‐Ray‐Responsive Mn ²⁺ Release via Scintillating Nanoparticles Drives cGAS‐STING Activation for Enhanced Radio‐Immunotherapy

ABSTRACT Radiotherapy (RT) represents a potent approach to activate the cyclic GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. However, this immune activation is typically transient and insufficient for long‐term tumor control. To overcome this limitation, we developed SCYS‐P@MnCO, an X‐ray‐responsive nanoplatform that integrates radioluminescent scintillating nanoparticles (SCNPs) with photosensitive manganese carbonyl complexes (MnCOs). This design enables the precise, spatiotemporally controlled release of Mn ²⁺ and carbon monoxide (CO) within the tumor microenvironment. The released Mn ²⁺ significantly sensitizes cGAS to cytosolic DNA, thereby amplifying STING signaling to promote interferon‐β secretion and dendritic cell maturation. When combined with RT, SCYS‐P@MnCO not only sensitizes tumors to radiation by CO but also induces a potent systemic immune response mediated by Mn ²⁺ . Together, this X‐ray‐responsive nanoplatform synergistically enhances radiosensitivity while amplifying innate immune activation, providing an effective strategy for advancing radio‐immunotherapy.