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

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 Mn²⁺ and carbon monoxide (CO) within the tumor microenvironment. The released Mn²⁺ 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 Mn²⁺. Together, this X-ray-responsive nanoplatform synergistically enhances radiosensitivity while amplifying innate immune activation, providing an effective strategy for advancing radio-immunotherapy.