Sorafenib-loaded metal-organic framework nanoparticles for anti-hepatocellular carcinoma effects through synergistically potentiating ferroptosis and remodeling tumor immune microenvironment

Sorafenib (Sor), a multi-kinase inhibitor, serves as the first-line systemic therapeutic drug for advanced hepatocellular carcinoma (HCC). Unfortunately, clinical benefit was confirmed in only a minority of patients, limiting clinical application of Sor. Using nanotechnology to enhance the therapeutic effect of anti-cancer drugs has become a major trend. Accordingly, a Fe(III)-based metal-organic framework (MOF) nanocarrier encapsulating Sor (Sor@Fe-MOF) with ferroptosis/immune activation functions was constructed for HCC therapy. <i>In vivo</i> and <i>in vitro</i> assays demonstrated that these prepared Sor@Fe-MOF nanoparticles (NPs) exhibited favorable therapeutic activities against HCC, characterized by increasing ferroptosis and remodeling tumor immune microenvironment. Compared with free Sor, Sor@Fe-MOF produced the additive effects that induce ferroptotic cell death in HCC cells through downregulating GPX4 and SLC7A11 and upregulating ACSL4. Using orthotopic tumor mouse model and humanized PBMC mouse model, we also found that Sor@Fe-MOF obviously activated the anti-HCC immunity via increasing tumor infiltration of CD8⁺ T cells. Upon internalization by CD8⁺ T lymphocytes, Sor@Fe-MOF effectively facilitated the activation and tumor penetration of these immune cells. No obvious morphological changes of mice organs implied the distinctive biological security during Sor@Fe-MOF treatment. Taken together, our findings highlighted the excellent capacity of Sor@Fe-MOF to facilitate ferroptosis and remodel immune microenvironment, consequentially improving therapeutic response of Sor. These prepared Sor@Fe-MOF NPs could be function as a promising alternative strategy for HCC treatment.