Self-Reported 2D Metal-Organic Nanosheet Pre-Catalyst for Bioorthogonally Anti-Tumor Immunotherapy.

Abstract

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.