Nanobiocatalyst-Driven Spatiotemporal Hydrogen Delivery Induces Dormancy Potentiated Catalytic Tumor Therapy.

Abstract

Colorectal cancer remains a therapeutic challenge due to systemic toxicity and the suboptimal efficacy of conventional therapies. Emerging evidence indicates that molecular hydrogen (H₂) exerts antitumor effects through proliferation suppression and induction of a "tumor dormancy" phenotype characterized by cell cycle arrest and metabolic quiescence. Capitalizing on this mechanism, we engineered a platinum-incorporated metal-organic framework (PM) that integrates H₂-mediated dormancy induction with 5-aminosalicylic acid (5-ASA)-potentiated NF-κB suppression. This system enables spatiotemporally light-controlled H₂ generation vis-à-vis water splitting, which disrupts redox homeostasis while synchronously releasing 5-ASA to block NF-κB nuclear translocation, thereby collectively inducing sustained proliferative arrest and immunosuppressive tumor microenvironment remodeling. Tumor-localized PM decomposition generates photosensitizers that amplify therapeutic efficacy through catalytic ROS storms, representing a dual-modality strategy that couples H₂-driven dormancy with ROS-mediated cytotoxicity. Mechanistic profiling reveals NF-κB suppression via modulation of the H₂/5-ASA-mediated redox-inflammatory axis, systematically validated through multiomics analyses across three tumor models and clinical specimens. H₂-induced dormancy sensitizes tumors to catalytic ROS attacks by potentiating metabolic vulnerabilities, while 5-ASA prevents dormancy from escaping through persistent NF-κB inactivation. This work introduces a nanomaterial-enabled approach to dormancy therapy, demonstrating the dual functionality of single-atom catalysts in precision catalytic H₂ generation and immunomodulatory integration. It proposes a framework for intercepting tumor progression via coordinated cell cycle control and microenvironmental reprogramming.