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

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

  • J Control Release. 2025 Jul 10:383:113814. doi: 10.1016/j.jconrel.2025.113814.
Fei Wu 1,  Chunxue Song 2,  Hanxiao Yin 3,  Ronglong Chen 2,  Guanyu Huang 3,  Jiajun Zhang 3,  Haimin Chen 2,  Li Lin 2,  Junqiang Yin 4,  Lisi Xie 5,  Weihai Liu 6
Affiliations

Affiliations

  • 1 Department of Musculoskeletal Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, China.
  • 3 Department of Musculoskeletal Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 4 Department of Musculoskeletal Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.. Electronic address: [email protected].
  • 5 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, China. Electronic address: [email protected].
  • 6 Department of Musculoskeletal Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.. Electronic address: [email protected].
PMID: 40319917 DOI: 10.1016/j.jconrel.2025.113814
Abstract

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.

Keywords

Bufalin; Ferroptosis; Homodimeric prodrugs; Metal-phenolic networks; Noncovalent interaction.

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