Multifunctional H 2 S‐activated metal‐organic framework systems for targeted colorectal cancer imaging and synergistic copper‐induced tumor regression

Abstract Stimuli‐responsive nanomaterials offer significant potential for enhancing diagnostic accuracy, optimizing therapeutic efficacy, and advancing precision theranostics. Hydrogen sulfide (H 2 S) was found to be upregulated in colorectal cancer, which endows it with an ideal endogenous trigger for tumor targeting. Here, we introduce a novel class of H 2 S‐activated metal‐organic framework (MOF) systems specifically designed for targeted colorectal cancer imaging and synergistic copper‐induced tumor regression. The Cu‐MOF nanoplatform demonstrated a rapid response to H 2 S at the tumor site, producing copper sulfide with strong near infrared absorption and activated PA signals. In vivo studies demonstrated remarkable tumor inhibition in an orthotopic colon cancer model with minimal side effects. The copper‐based MOFs theranostic nanosystem effectively reduced protein lipoylation and Fe‐S cluster protein levels (FDX1), triggering cuproptosis. This study presents a novel strategy for designing multifunctional nanoparticles for synergistic PA/CDT/PTT/cuproptosis theranostics.