Bioorthogonal Cu-MOF nanocatalyst enables GSH-triggered in situ drug synthesis for xCT-driven ferroptosis in colorectal cancer.

Despite advances in colorectal cancer (CRC) therapy, treatment outcomes remain limited by a refractory tumor microenvironment (TME) that restores redox balance and suppresses ferroptotic damage. To address this challenge, we developed HMOI, a butyrate-modulated copper metal-organic framework (Cu-MOF) designed to enable TME-activated ferroptosis through the in situ synthesis of a novel xCT inhibitor (SLZC96) via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Butyrate-mediated coordination modulation yields uniform, redox-responsive nanocrystals that exploit elevated glutathione (GSH) levels in tumors to drive Cu(II)/Cu(I) cycling, deplete intracellular GSH, amplify lipid peroxidation, and induce ferroptotic cell death accompanied by immunogenic stress signaling. Hyaluronic acid functionalization further enhances CD44-mediated tumor accumulation, enabling precise intratumoral activation of SLZC96. In vivo, HMOI treatment increased CD8 T-cell infiltration and IFN-γ production, reflecting enhanced antitumor immune activity alongside ferroptotic pressure. These combined effects resulted in significant tumor regression with minimal systemic toxicity. Overall, HMOI integrates butyrate-regulated MOF engineering, redox-driven catalytic activation, and localized xCT blockade to establish a ferroptosis-based nanoplatform that simultaneously disrupts CRC redox defenses and strengthens antitumor immune responses.