Trimetallic Cu-Zn-Fe Layered Double Hydroxide Nanocarrier Enabling On-Demand Anticancer Drug Release with Prolonged Therapeutic Windows for Precision Oncology.

Clinical oncology faces a critical technological bottleneck driven by the rapid emergence of therapy-resistant tumors. Melanoma, in particular, remains a highly aggressive malignancy with pronounced metastatic potential and poor responsiveness to traditional therapy, signify the demand for advanced therapeutic strategies. Herein, we report a multifunctional nanoplatform integrating ternary layered double hydroxides (LDHs) with an injectable hydrogel system for localized and controlled melanoma therapy. The engineered trimetallic Cu-Zn-Fe LDHs (CZF) exhibit tunable physicochemical properties, enabling efficient drug intercalation, enhanced structural stability, and stimuli-responsive release within the tumor microenvironment. Doxorubicin (Dox) loaded LDHs (CZF@Dox) demonstrate high loading efficiency and sustained release, minimizing premature leakage and systemic toxicity. Computational insights from molecular dynamics and machine learning-assisted modeling reveal optimized host-guest interactions for improved delivery performance. In vitro studies confirm excellent biocompatibility toward normal 3T3-L1 cells (∼10% cell death at 20 μg/mL, 72 h), alongside significant cytotoxicity against B16F10 and SiHa cancer cells (∼80-85% cell death at the same conditions). In vivo evaluation further demonstrates effective tumor suppression with prolonged dosing intervals (96 h). Overall, this platform offers a predictive, minimally invasive, and efficient strategy for next-generation melanoma therapy.