NIR‐Activatable, Sequence‐Specific Metal‐Nucleic Acid Scaffolds for Responsive Uncaging

Abstract Precise molecular activation with both analyte specificity and spatiotemporal control remains a major challenge in responsive diagnostics, targeted therapies, and the study of complex biological systems. Traditional photo‐uncaging strategies offer excellent temporal resolution but suffer from limited tissue penetration and poor biological specificity, while analyte‐responsive platforms provide molecular selectivity without external control. Here, we introduce sequence‐responsive diagnostic uncaging—a unique approach that integrates nucleic acid recognition with near‐infrared (NIR)‐triggered molecular activation within a metal‐nucleic acid scaffold. This platform is built upon a first‐of‐its‐kind Pt(IV)‐DNA molecular scaffold, modularly assembled via click chemistry, and integrates a Pt(IV)‐caged reporter, a nucleic acid recognition domain, and an NIR antenna (e.g., IR800). Notably, DNA‐mediated electron transfer (DNA‐MET) provides a long‐range ET pathway to direct photoreduction of the Pt(IV) centers, enabling “responsive uncaging” that occurs only upon hybridization with a fully complementary DNA or miRNA strand. Upon NIR irradiation, the duplexed nucleic acid system facilitates electron transfer from the excited antenna to Pt(IV), triggering the release of fluorescent reporters. Using two Pt(IV)‐caged fluorophores (MCA and BDP), we demonstrate efficient uncaging and high sequence specificity in both solution and live cells. This platform offers a powerful and versatile photochemical tool that seamlessly bridges diagnostics and molecular activation, with broad implications for precision medicine, targeted drug delivery, and next‐generation biosensing technologies.