Metal phenolic networks-driven bufalin homodimeric prodrug nano-coassemblies for ferroptosis-augmented tumor therapy

Poor bioavailability and dose-limiting cardiotoxicity persistently hinder the clinical application of bufalin (BF). Conventional BF-based nanoagents have shown promise in tackling these challenges, yet advanced nanostrategies with further improved performance and clinical accessibility still await development. Herein, we introduce a novel cooperative nanoparadigm based on disulfide-linked BF homodimeric prodrugs (SBF) and metal-phenolic networks (MPNs). This strategy achieves high drug-loading capacity and structural stability. Stability perturbation experiments reveal that hydrophobic interactions, electrostatic adsorption, and coordination bonds synergistically drive co-assembly of SBF and MPNs. The resultant nanopartieles (MSBNAs) exhibit prolonged circulation kinetics, tumor-selective accumulation, and pH/GSH dual-responsive properties, effectively mitigating BF-induced cardiotoxicity. Further antitumor mechanistic investigations unveil that MSBNAs amplify BF-induced ferroptosis through a dual assault of oxidative stress and iron overload induced jointly by MPNs-delivered exogenous iron and BF-triggered endogenous iron. This increased ferroptosis endows MSBNAs with superior suppression of tumor growth and lung metastasis, maintaining excellent biocompatibility without cardiotoxicity. Our work not only establishes a promising candidate platform to surmount the therapeutic hurdles of BF but also enriches the design landscapes of co-assembled nanomedicines, thereby laying a foundation for the clinical translation of BF and other antitumor drugs.