*Article* **Tumor Microenvironment-Responsive Magnetic Nanofluid for Enhanced Tumor MRI and Tumor multi-treatments**

**Liangju Sheng 1,†, Xuanlei Zhu 2,†, Miao Sun <sup>2</sup> , Zhe Lan <sup>1</sup> , Yong Yang <sup>3</sup> , Yuanrong Xin 2,\* and Yuefeng Li 1,\***


† These authors contributed equally to this work.

**Abstract:** We prepared a tumor microenvironment-responsive magnetic nanofluid (MNF) for improving tumor targeting, imaging and treatment simultaneously. For this purpose, we synthesized sulfonamide-based amphiphilic copolymers with a suitable p*K*<sup>a</sup> at 7.0; then, we utilized them to prepare the tumor microenvironment-responsive MNF by self-assembly of the sulfonamide-based amphiphilic copolymers and hydrophobic monodispersed Fe3O<sup>4</sup> nanoparticles at approximately 8 nm. After a series of characterizations, the MNF showed excellent application potential due to the fact of its high stability under physiological conditions and its hypersensitivity toward tumor stroma by forming aggregations within neutral or weak acidic environments. Due to the fact of its tumor microenvironment-responsiveness, the MNF showed great potential for accumulation in tumors, which could enhance MNF-mediated magnetic resonance imaging (MRI), magnetic hyperthermia (MH) and Fenton reaction (FR) in tumor. Moreover, in vitro cell experiment did not only show high biocompatibility of tumor microenvironment-responsive MNF in physiological environment, but also exhibit high efficacy on inhibiting cell proliferation by MH-dependent chemodynamic therapy (CDT), because CDT was triggered and promoted efficiently by MH with increasing strength of alternating magnetic field. Although the current research is limited to in vitro study, these positive results still suggest the great potential of the MNF on effective targeting, diagnosis, and therapy of tumor.

**Keywords:** tumor microenvironment-responsive; magnetic nanofluid; improved magnetic resonance imaging; neutral-responsive Fenton reaction; enhanced chemodynamic therapy
