Nanoparticle‐Based MRI‐Guided Tumor Microenvironment Heating via the Synergistic Effect of Ferroptosis and Inhibition of TGF‐β Signaling

Abstract Although induction of ferroptosis and inhibition of transforming growth factor‐ β (TGF‐ β ) signaling are both effective ways to reform the tumor microenvironment (TME) and render low‐immunogenic tumors responsive to immune checkpoint inhibitor therapy, dose‐limiting side effects remain major obstacles hindering their clinical application. Herein, novel sorafenib and anti‐TGF‐ β antibody loaded Fe 3 O 4 /Gd 2 O 3 hybrid nanoparticles with conjugation of arginine‐glycine‐aspartic dimer (FeGd‐HN@Sorafenib@TGF‐ β ‐antibody@RGD2, FG‐STR) are developed. Sorafenib significantly enhances FeGd‐HN‐triggered ferroptosis and improves maturation and phagocytosis of dendritic cells (DCs) by inducing damage‐associated molecular patterns released from ferroptotic cancer cells, while the anti‐TGF‐ β antibody further synergizes with enhanced ferroptosis to promote DC maturation and the recruitment of CD8 + T cells, thus heating the TME. Moreover, the incorporation of RGD2 facilitates the uptake of the FG‐STR in tumor cells which lead to a significant dosage reduction of both sorafenib and anti‐TGF‐ β antibody to avoid dose‐limiting toxicities. Finally, in vitro and in vivo experiments show that FG‐STR has significantly superior intrinsic magnetic resonance imaging (MRI) capability than that of Gadovist, effectively inhibits tumor growth and lung metastasis, and increases the efficacy of anti‐programmed cell death‐1 treatment. Taken together, this study provides a promising strategy for new advanced MRI‐guided TME heating therapies.