Shenqiang Wang^a,b,1, Letao Yang^b,1, Hyeon-Yeol Cho^b, Sy-Tsong Dean Chueng^b, Hepeng Zhang^b, Qiuyu Zhang^a,*, Ki-Bum Lee^b,c,*

^a MOE Key Laboratory of Material Physics and Chemistry Under Extraordinary Conditions, School of Natural and Applied Sciences, Northwestern Polytechnical University, Xi'an, 710129, China
^b Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, 08854, USA
^c Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, 02447, South Korea

¹These authors have contributed equally to this manuscript.

^*Corresponding author : Qiuyu Zhang, Ki-Bum Lee

Chemodynamic therapy (CDT) has recently emerged as a promising treatment for cancer due to the high specificity of CDT towards tumor microenvironment (TME). However, the low efficiency of reactive oxygen species (ROS) generation and the robust ROS defensive mechanisms in cancer cells remain critical hurdles for current CDT. Addressing both challenges in a single platform, we developed a novel redox and light-responsive (RLR) nanoparticle with a core-shell structure. Remarkably, our hierarchical RLR nanoparticle is composed of an ultrasmall Fe3O4 nanoparticle engineered framework of hollow carbon matrix core and a nanoflower-like MnO2 shell. Under the abundant overexpressed glutathione (GSH) and acidic nature in TME, the RLR nanoparticle was programmed to degrade and self-activate CDT-induced cancer-killing by accelerating ROS generation via overcoming the ROS defensive mechanisms based on the depletion of intracellular GSH, the sequential production of theranostic ion species (e.g., Mn2+ and Fe2+), a spatiotemporal controllable photothermal hyperthermia and a redox triggered chemotherapeutic drug release. Additionally, the carbon framework of RLR nanoparticle could collapse by leaching of iron ions. An excellent selective and near-complete tumor suppression based on the RLR nanoparticles through a strong synergy between CDT, PTT and anti-cancer drugs was demonstrated via in vitro and in vivo anti-tumoral assays.

Keywords : Programmed degradation; Tumor microenvironment; Hierarchical nanoparticle; Self-activated chemodynamic therapy; Photothermal therapy; Drug delivery