Developing a Ferric(III) Agent for Targeted Inhibition of Growth and Metastasis of Triple-Negative Breast Cancer Based on Human Serum Albumin by Chemodynamic Therapy-Driven Synergistic Therapy.

Triple-negative breast cancer (TNBC) remains challenging due to its aggressiveness and the lack of targeted therapies. In this study, we proposed designing a ferric (Fe) agent based on human serum albumin (HSA) for chemodynamic therapy-driven synergistic therapy. To this end, we not only optimized a series of Fe(III) compounds to obtain Fe4, which has remarkable toxicity against TNBC cells, but we also constructed the HSA-Fe4 NPs delivery system. Structural analysis revealed that Fe4 binds within the IB subdomain of HSA, with His-146 coordinating the iron center. Importantly, Fe4/HSA-Fe4 NPs significantly suppressed the metastasis and growth of TNBC in vivo. Moreover, we elucidated the mechanisms by which Fe4/HSA-Fe4 NPs inhibited the growth and metastasis of TNBC: inducing Fenton reaction-mediated chemodynamic therapy, inducing ferroptosis, and tri-activating the immune response through the activation of the cGAS-STING pathway, the induction of immunogenic cell death, and the repolarization of M2 macrophages.