TME-Responsive Nanoplatform with Glutathione Depletion for Enhanced Tumor-Specific Mild Photothermal/Gene/Ferroptosis Synergistic Therapy

Yuhang Tian,1 Xiang He,1 Yanchi Yuan,1 Shijie Zhang,2 Chunyue Wang,1 Jialin Dong,1 Zhao Liu,1 Hui Jing1 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 2Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of ChinaCorrespondence: Hui Jing, Department of Ultrasound, Harbin Medical University Cancer Hospital, 150 Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Email [email protected]: Triple negative breast cancer (TNBC) is one of the worst prognosis types of breast cancer that urgently needs effective therapy methods. However, cancer is a complicated disease that usually requires multiple treatment modalities.Methods: A tumor microenvironment (TME)-responsive PFC/TRIM37@Fe-TA@HA (abbreviated as PTFTH) nanoplatform was constructed by coating Fe3+ and tannic acid (TA) on the surface of TRIM37-siRNA loaded phase-transition perfluorocarbon (PFC) nanodroplets and further modifying them with hyaluronic acid (HA) to achieve tumor-specific mild photothermal/gene/ferroptosis synergistic therapy (MPTT/GT/ Ferroptosis) in vitro. Once internalized into tumor cells through CD44 receptor-mediated active targeting, the HA shell of PTFTH would be preliminarily disassembled by hyaluronidase (HAase) to expose the Fe-TA metal-phenolic networks (MPNs), which would further degrade in response to an acidic lysosomal environment, leading to HAase/pH dual-responsive release of Fe3+ and PFC/TRIM37.Results: PTFTH showed good biocompatibility in vitro. On the one hand, the released Fe3+ could deplete the overexpressed glutathione (GSH) through redox reactions and produce Fe2+, which in turn converts endogenous H2O2 into highly cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). On the other hand, the local hyperthermia generated by PTFTH under 808 nm laser irradiation could not only improve CDT efficacy through accelerating the Fe2+-mediated Fenton reaction, but also enhance TRIM37-siRNA delivery for gene therapy (GT). The consumption of GSH and accumulation of •OH synergistically augmented intracellular oxidative stress, resulting in substantial tumor cell ferroptosis. Moreover, PTFTH possessed outstanding contrast enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) ability.Conclusion: This PTFTH based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect in vitro and has the potential to be translated into clinical application for tumor therapy in future.Keywords: mild photothermal therapy, gene therapy, ferroptosis, synergistic therapy, multimodal imaging