Engineered Metal–Organic Framework with Stereotactic Anchoring and Spatial Separation of Porphyrins for Amplified Ultrasound‐Mediated Pyroptosis and Cancer Immunotherapy

Abstract Ultrasound‐mediated reactive oxygen species (ROS) generation is pivotal in specifically inducing pyroptosis of tumor cells. However, the effectiveness of pyroptosis is generally hindered by the constraints of ROS generation efficiency. Herein, a new porphyrin‐based metal–organic framework (Fe(TCPP)‐MOF) was rationally designed via an innovative dual‐solvent strategy to amplify ROS generation for ultrasound‐controlled pyroptosis. The crystal structure of Fe(TCPP)‐MOF was elucidated by continuous rotation electron diffraction technique, revealing its regular and rigid conformation. The porphyrin molecules were precisely oriented and firmly confined within the scaffold, effectively restricting intramolecular motion. The ample distance of 6.8 Å between two porphyrin molecules, combined with the interaction region indicator visualization, confirmed the absence of π–π stacking interactions in the Fe(TCPP)‐MOF framework, thereby avoiding the aggregation‐caused quenching effect. Furthermore, the permanent porosity and expansive surface area of Fe(TCPP)‐MOF enhanced its interaction with oxygen. These ingenious structural features endowed Fe(TCPP)‐MOF with a unique ability to generate a large amount of singlet oxygen under ultrasound activation. Meanwhile, the impetus of ultrasound also accelerated the rate of the Fenton reaction catalyzed by iron ions, significantly boosting the generation of hydroxyl radicals. Benefiting from the dual amplification of ROS, Fe(TCPP)‐MOF could efficiently induce tumor cells pyroptosis under ultrasound stimulation, thereby intensifying the potency of cancer immunotherapy.