Antitumor Efficacy and Immunomodulation of H‑Ferritin Nanocaged Doxorubicin for Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains a major therapeutic challenge due to its aggressiveness and lack of targeted treatment options. Ferritin-encapsulated doxorubicin (HFn-Dox) is a nanocarrier-based formulation with documented tumor targeting activity and antitumor potential. In this study, we advance its clinical relevance by evaluating the HFn-Dox efficacy and toxicity profile at therapeutic dosing in patient-derived xenograft (PDX) and syngeneic TNBC models. HFn-Dox significantly outperformed free Dox by suppressing tumor growth and reducing metastatic spreading in both the models. When compared with free Dox and the clinically approved pegylated liposomal doxorubicin (Lipo-Dox), HFn-Dox also displayed a more favorable cardiotoxicity profile, which allowed dose intensification without compromising safety. Additionally, HFn-Dox modulated the tumor immune microenvironment in immunocompetent mice by enhancing intratumoral infiltration of Tlymphocytes and M1 macrophage polarization. In vitro, HFn-Dox preserved the T cell viability and prevented exhaustion. It also promoted the activation of macrophages and dendritic cells, contrasting with the immunosuppressive effects of free Dox. Altogether, our results demonstrate that HFn-Dox can increase the therapeutic index of doxorubicin by combining improved tumor delivery, reduced off-target toxicity, and immune system preservation. These features support the translational potential of HFn-Dox as a safer and more effective nanochemotherapy for TNBC.