Modulated Ultrasmall γ‐Fe₂O₃ Nanocrystal Assemblies for Switchable Magnetic Resonance Imaging and Photothermal‐Ferroptotic‐Chemical Synergistic Cancer Therapy

Abstract Ferroptosis is recently discovered programmed cell death, induced by cellular ferrous ion bursts and subsequent Fenton reactions. The iron source in tumor cells is limited due to tightly controlled iron metabolism. Since hierarchical iron architecture is rarely considered in ferroptosis cancer treatment, multilayer Fe₂O₃ architectures (UF@PPDF NPs) are developed by modulating ultra‐small γ‐Fe₂O₃ nanocrystal assemblies, and further conjugating cancer cell targeting folic acid (FA), chemotherapeutic drug doxorubicin (Dox). Hierarchically assembled γ‐Fe₂O₃ nanocrystal facilitates switchable magnetic resonance imaging (MRI), much enhanced ferroptosis efficiency, and very high second near‐infrared (NIR‐II) photothermal conversion. For MRI, UF@PPDF nanoparticles (NPs) enables clearly visualized tissues in terms of size and compactness, with dynamic T2‐T1 imaging switching. UF@PPDF NPs exhibits highly efficient photothermal therapy (PTT) upon NIR‐II irradiation, together with controlled release of ferric ions and Dox, thus achieving PTT‐chemotherapy‐ferroptosis trifunctional synergistic cancer therapy for tumor ablation. RNA sequencing analyses of differentially expressed genes implies a multifaceted role for this therapy in cancer cell signaling. Cellular respiration and electron transport are significantly upregulated, while the epigenetic pathways, including chromatin modification and RNA transcription activity are severely downregulated, with an overall effect of cellular apoptosis. Thus, γ‐Fe₂O₃ architectures provide new possibility for highly efficient deep tumor treatment.