Self‐Reported 2D Metal–Organic Nanosheet Pre‐Catalyst for Bioorthogonally Anti‐Tumor Immunotherapy

Transition metal‐mediated bioorthogonal reactions face significant challenges, including limited catalytic stability in biological media, sensitivity to environmental conditions, high toxicity, and unpredictable reactions with the prodrugs. Herein, we present a self‐reporting biopalladium pre‐catalyst, which simultaneously generates catalytic activity through an in situ ligand exchange process in tumor tissue and a turn‐on near‐infrared fluorescence signal to indicate the optimal reaction time point with the prodrug. Ultrathin 2D metal–organic nanosheet (Pd‐BDP) is crafted as a bioorthogonal pre‐catalyst with good biocompatibility, which servesd as a reservoir of Pd(II) and avoids its rapid deactivation in living systems. Pd‐BDP is activated by electron‐poor tri(2‐furyl) phosphine (TFP) to generate a Pd complex with a decaging yield of 63.3% under complex physiological conditions, and the process could be simultaneously visualized by NIR fluorescence signals from released BDP photosensitizer. Combination treatment of the immunotherapeutic agonist prodrug (R848) and PDT/PTT‐induced ICD facilitates strong antitumor immunity and reduces systemic inflammation, leading to precise inhibition of primary tumor growth and lung metastasis in the mouse model. This study thus opens a new avenue for rational design of bioorthogonal pre‐catalysts with a good balance between biocompatibility, stability, and catalytic activity, which underlines its potential to improve the safety and efficacy of synergistically bioorthogonal immunotherapy.