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

Abstract 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 (CuO 2 ) encapsulated with complex (Zn‐F) shell of zinc (Zn 2+ ) and fluorimidazole (F). The TME‐responsive decomposition of CuO 2 releases Cu 2+ and H 2 O 2 , where Cu 2+ coordinates with fluorimidazole, resulting in the release of Zn 2+ 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), 19 F magnetic resonance imaging ( 19 F‐MRI), and photothermal therapy (PTT). Moreover, they catalyze the conversion of both self‐supplied H 2 O 2 and endogenous H 2 O 2 into highly toxic hydroxyl radicals, enabling chemodynamic therapy. Notably, the released Zn 2+ 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.