A Reactivity‐Tunable Self‐Immolative Design Enables Histone Deacetylase‐Targeted Imaging and Prodrug Activation.

Histone deacetylase (HDAC)‐targeted probes and prodrugs are crucial for cancer theranostics. We developed a self‐immolative design that enables in vivo activatable near‐infrared fluorescence (NIRF) and photoacoustic (PA) imaging and prodrug release in response to HDAC. This design comprises a phenyl ester linker with tunable reactivity, facilitating efficient release of caged fluorophores/drugs upon deacetylation. We engineered a new fluorophore using a spirocyclic xanthene scaffold with ring‐open property, affording NIRF/PA detection with high contrast. We showed that a nitro‐substituted self‐immolative linker allows sensitive NIRF/PA in vivo imaging of HDAC with minimal interference. A highly efficient prodrug system was further developed for targeted therapy in HDAC‐overexpressed triple negative breast tumors in mice. Our study provides a valuable paradigm for HDAC‐targeted NIRF/PA imaging and prodrug release in vivo, highlighting its potential for bioimaging and drug development. [ABSTRACT FROM AUTHOR]