Zinc Gallate Nanoclusters-Mediated Enhanced Metalloptosis in Melanoma

As one of the most malignant tumors, metastatic melanoma essentially requires the regulation of the lysosomal cation channel, transient receptor potential mucolipin channel 1 (TRPML1), which is also involved in the participation of various ions especially zinc ions. This perfectly aligns with the advanced therapeutic approach based on nanomaterials, because nanomaterials can easily integrate multiple metal elements to disrupt the internal homeostasis of various ions, eventually inhibiting the cell growth of metastatic melanoma. Hence, based on our previously proposed metalloposis strategy, herein, zinc gallate-based nanoclusters (ZGOCs) containing both zinc and gallium were developed, capable of inducing metalloposis. Responded to weakly-acid tumor microenvironment (TME), ZGOCs could effectively release gallium ions that triggered ferroptosis through depleting glutathione (GSH) and increasing lipid peroxidation (LPO) levels. Moreover, the released zinc ions co-treated with ML-SA5, a TRPML-specific agonist, further promoted lysozincrosis. In addition, ZGOCs exhibited rechargeable afterglow luminescence, which facilitated in vivo clearer diagnostic images with high contrast for more accurate detection of tumor boundaries. Collectively, ZGOCs in combination with ML-SA5 significantly suppressed tumor growth with favorable biosafety, providing a promising metalloptosis-based strategy for the treatment of metastatic melanoma.