In Situ Coordination‐Assembly Nano‐Drugs/Probes for Enhanced Tumor Retention and Responsive Release

Improving the retention of probes/drugs in tumor and achieving tumor microenvironment (TME) responsive sustained release are highly desirable but face great challenges. Here, we report a TME-stimulated coordination assembly strategy to enhance the retention in tumor and TME-responsive sustained release of nano-probes/drugs consisting of copper peroxide (CuO₂) encapsulated with complex (Zn-F) shell of zinc (Zn²⁺) and fluorimidazole (F). The TME-responsive decomposition of CuO₂ releases Cu²⁺ and H₂O₂, where Cu²⁺ coordinates with fluorimidazole, resulting in the release of Zn²⁺ and the formation of Cu-F in situ. These secondary self-assembled Cu-F nanoplatforms serve as a theranostic agent, retaining at the tumor site for TME-responsive photoacoustic imaging (PAI), ¹⁹F magnetic resonance imaging (¹⁹F-MRI), and photothermal therapy (PTT). Moreover, they catalyze the conversion of both self-supplied H₂O₂ and endogenous H₂O₂ into highly toxic hydroxyl radicals, enabling chemodynamic therapy. Notably, the released Zn²⁺ activates the cGAS-STING pathway of immune cells under TME, enhancing the perception of immunogenic cell death. In vivo experimental results suggest that this study provides a promising in situ coordination assembly strategy for developing TME-responsive nanotheranostics with enhanced tumor retention and theranostic performance.