A multienzyme-mimicking nanoplatform induces disulfidptosis/cuproptosis/apoptosis for tumor therapy

The distinct characteristics of the tumor microenvironment (TME) provide great potential for valuable tumor-targeting therapies using enzymes. Herein, MOF-818 with a diameter of 139 nm is synthesized and exhibits multienzyme-mimicking activities, including peroxidase, catalase, glutathione oxidase, glucose oxidase, superoxide dismutase, and tyrosinase (TYR)-like activities. Based on these enzymatic activities, MOF-818 catalyzes an entire process that progresses through self-generated substrates and cyclic catalytic reactions, and notably induces TME remodeling. Synchronously, for the first time reported in nanozymes, MOF-818 activates the prodrug acetaminophen (APAP) through its TYR-like activity, further increasing reactive oxygen species accumulation. These features contribute to MOF-818's antitumor activity by activating multiple combined programmed cell death pathways: apoptosis, disulfidptosis, and cuproptosis. The MOF-818 nanoplatform, 3-methyladenine (3-MA), THP-1 cell membranes, and a fusion protein of Fc and TNF-related apoptosis-inducing ligand (Fc-TRAIL) were integrated to construct 3-MA@MOF-818@CM-Fc-TRAIL nanoparticles (3MCT NPs). These NPs target tumor cells and, when coupled with APAP, show efficient therapeutic effects with good biosafety. Our findings indicate that the MOF-818 could function as a multienzyme-mimetic scaffold for engineering targeted nanoplatforms that co-deliver combinatorial therapeutic agents, thereby enabling combined antitumor therapy.