Bimetal‐Biligand Frameworks for Spatiotemporal Nitric Oxide‐Enhanced Sono‐Immunotherapy

Abstract Sonodynamic therapy can trigger immunogenic cell death to augment immunotherapy, benefiting from its superior spatiotemporal selectivity and non‐invasiveness. However, the practical applications of sonosensitizers are hindered by their low efficacy in killing cancer cells and activating immune responses. Here, two US Food and Drug Administration‐approved drug ligands (ferricyanide and nitroprusside) and two types of metals (copper/iron) are selected to construct a bimetal‐biligand framework (Cu[PBA‐NO]). Through elaborate regulation of multiple metal/ligand coordination, the systemically administered Cu[PBA‐NO] nanoagent shows sono‐catalytic and NO release ability under ultrasound irradiation, which can be used for effective sono‐immunotherapy. Moreover, Cu[PBA‐NO] can downregulate intracellular glutathione levels that would destroy intracellular redox homeostasis and facilitate reactive oxygen species accumulation. The released tumor‐associated antigens subsequently facilitate dendritic cell maturation within the tumor‐draining lymph node, effectively initiating a T cell‐mediated immune response and thereby bolstering the capacity to identify and combat cancer cells. This study paves a new avenue for the efficient cancer sono‐immunotherapy.