Bimetallic MnZnSX Nanotheranostics for Self‐Activatable Chemo‐Immunotherapy of Hepatocellular Carcinoma via H₂S‐Triggered Arsenic Prodrug Activation and Binary cGAS‐STING Pathway Modulation

Arsenic prodrug-loaded MnZnS_X nanorods (As-MnZnS_X NRs) enhance hepatocellular carcinoma treatment by binary-cooperative activation of the cGAS-STING pathway, combining immune modulation with targeted cytotoxicity and enabling real-time MRI monitoring, thus improving efficacy and safety.

Abstract

Arsenic trioxide (As₂O₃) has long been utilized in traditional Chinese medicine due to its therapeutic properties. While it exhibits potent anticancer activity, its clinical application is hindered by systemic toxicity and limited tissue specificity. In this study, an advanced therapeutic approach is developed using arsenic prodrug-loaded bimetallic sulfide MnZnS_X nanorods (As-MnZnS_X NRs) to enhance both the efficacy and safety of As₂O₃ in hepatocellular carcinoma treatment. These nanorods are engineered to release Mn²⁺ and H₂S within the tumor microenvironment, facilitating binary-cooperative activation of the cGAS-STING pathway. This dual activation mechanism enhances immune responses while converting the arsenic prodrug into its cytotoxic form, As^III. The results demonstrate that Mn²⁺ amplifies the cGAS-STING pathway by inducing TBK1 phosphorylation and IRF3 activation, leading to dendritic cell maturation and improved tumor antigen cross-presentation. Simultaneously, H₂S promotes prodrug conversion and enhances immune activation, collectively driving binary stimulation of the cGAS-STING pathway. This strategy significantly augments the antitumor efficacy of As₂O₃ by integrating immune modulation with targeted cytotoxic effects. Furthermore, MnZnS_X nanorods enable in vivo MRI, allowing real-time monitoring of treatment progression. This study represents a substantial advancement in liver cancer therapy by integrating chemoimmunotherapy with diagnostic imaging, thereby improving therapeutic precision while minimizing systemic toxicity.