Tumor‐Microenvironment‐Triggered Ion Exchange of a Metal–Organic Framework Hybrid for Multimodal Imaging and Synergistic Therapy of Tumors

Abstract Nanotheranostic agents (NTAs) that integrate diagnostic capabilities and therapeutic functions have great potential for personalized medicine, yet poor tumor specificity severely restricts further clinical applications of NTAs. Here, a pro‐NTA (precursor of nanotheranostic agent) activation strategy is reported for in situ NTA synthesis at tumor tissues to enhance the specificity of tumor therapy. This pro‐NTA, also called PBAM, is composed of an MIL‐100 (Fe)‐coated Prussian blue (PB) analogue (K₂Mn[Fe(CN)₆]) with negligible absorption in the near‐infrared region and spatial confinement of Mn²⁺ ions. In a mildly acidic tumor microenvironment (TME), PBAM can be specifically activated to synthesize the photothermal agent PB nanoparticles, with release of free Mn²⁺ ions due to the internal fast ion exchange, resulting in the “ON” state of both T₁‐weighted magnetic resonance imaging and photoacoustic signals. In addition, the combined Mn²⁺‐mediated chemodynamic therapy in the TME and PB‐mediated photothermal therapy guarantee a more efficient therapeutic performance compared to monotherapy. In vivo data further show that the pro‐NTA activation strategy could selectively brighten solid tumors and detect invisible lymph node metastases with high specificity.