Peritoneal metastasis (PM) in colorectal cancer (CRC) is characterized by a highly immunosuppressive microenvironment and poor clinical outcomes, which are further exacerbated by elevated SERPINE1 (PAI-1) expression and the restrictive peritoneal-plasma barrier. To overcome these multifactorial challenges, we engineered a cobalt-based, redox-responsive smart hydrogel system (CoGel@TBB) for the spatiotemporal co-delivery of the PAI-1 inhibitor TBB and cobalt nanoparticles directly to the peritoneal cavity. Upon adhesion to the tumor surface, the hydrogel rapidly releases TBB to inhibit PAI-1, effectively remodeling the fibrotic stroma and enhancing tumor tissue permeability. Concurrently, the sustained release o... More
Peritoneal metastasis (PM) in colorectal cancer (CRC) is characterized by a highly immunosuppressive microenvironment and poor clinical outcomes, which are further exacerbated by elevated SERPINE1 (PAI-1) expression and the restrictive peritoneal-plasma barrier. To overcome these multifactorial challenges, we engineered a cobalt-based, redox-responsive smart hydrogel system (CoGel@TBB) for the spatiotemporal co-delivery of the PAI-1 inhibitor TBB and cobalt nanoparticles directly to the peritoneal cavity. Upon adhesion to the tumor surface, the hydrogel rapidly releases TBB to inhibit PAI-1, effectively remodeling the fibrotic stroma and enhancing tumor tissue permeability. Concurrently, the sustained release of cobalt ions catalyzes endogenous hydrogen peroxide into highly cytotoxic reactive oxygen species (ROS), triggering tumor cell pyroptosis and the subsequent release of mitochondrial DNA (mtDNA). Crucially, the released cobalt ions also function as STING agonists, synergizing with the mtDNA to robustly activate the cGAS-STING signaling pathway. Both in vitro and in vivo evaluations demonstrated that CoGel@TBB significantly augments dendritic cell maturation and CD8+ T cell infiltration, successfully reversing the immunosuppressive landscape. Consequently, this localized, multi-strategy delivery platform achieved remarkable tumor suppression and extended survival in murine models of CRC peritoneal metastasis, offering a highly promising clinical paradigm for amplifying anti-tumor immunity.
