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

Abstract 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.