Disentangled Hydrogel With Rare Earth‐Activated Multi‐Enzymatic Activity Reverses the Pathological Vicious Cycle by Establishing a Closed‐Loop for Postoperative Melanoma Treatment

ABSTRACT Full‐thickness skin defects and tumor cells' apoptosis resistance are major contributors to postoperative melanoma recurrence. Current postoperative adjuvant strategies typically target single factors, overlooking complex pathological crosstalk among residual tumors and wound healing via patient‐specific heterogeneity. This hinders the realization of precise, adaptive interventions. To overcome these challenges, we developed a multi‐dimensionally enhanced nanocomposite hydrogel (M 3%Cu/3%Eu @A GOC) with active/passive interactive properties. Upon mild photothermal activation (∼45°C), this hydrogel disentangles to undergo structural remodeling and adaptively fills deep wounds. It also enables the adaptive active/passive diffusion of M 3%Cu/3%Eu @A in response to disease progression. At residual tumor foci, near‐infrared light causes “electronic energy level transfer”, triggering a cyclic tumoricidal cascade involving O 2 release, ·OH generation, and glutathione consumption. Using tumor‐expressed tyrosinase and cascade‐supplemented O 2 , the system synergistically activates the non‐toxic prodrug into toxic benzoquinone metabolites, further inhibiting cellular antioxidant defense. Inducing hybrid cell death via cuproptosis, ferroptosis, and photothermal effects, it effectively eliminates drug‐resistant tumor cells. In physiologically relevant contexts, the hydrogel releases epidermal reconstruction‐facilitating dissolution products (SiO 3 2 − , Ca 2 + , Eu 3 + ) while reprogramming macrophage polarization into a tissue‐reparative phenotype. These multi‐modal, multi‐level synergies transform a pathological vicious cycle into a therapeutic virtuous cycle, offering a novel closed‐loop strategy for the postoperative management of melanoma.