DNA-Free Guanosine-Based Polymer Nanoreactors with Multienzyme Activities for Ferroptosis–Apoptosis Combined Antitumor Therapy
Xiaonong Zhang, Yingqi Zhang, Xueli Lv, Peng Zhang, Chunsheng Xiao, Xuesi Chen
Abstract
Concurrent induction of ferroptosis and apoptosis by enzyme catalysis represents a promising modality for cancer therapy. Inspired by the structures of DNA and G-quadruplex/hemin DNAzyme, a DNA-free guanosine-based polymer nanoreactor (HPG@hemin-GOx) is prepared as a ferroptosis–apoptosis inducer by a one-step assembly of phenylboronic acid-modified hyaluronic acid (HA-PBA), guanosine (G), hemin, and glucose oxidase (GOx). HPG@hemin-GOx shows GOx, peroxidase (POD)-like, catalase (CAT)-like, and glutathione peroxidase (GPX)-like activities. The GOx activity of the nanoreactor can increase intracellular hydrogen peroxide (H 2 O 2 ) levels by oxidizing glucose in the presence of oxygen. The POD-like activity of HPG@hemin-GOx can then induce the generation of hydroxyl radicals utilizing generated H 2 O 2 . Meanwhile, the production of oxygen by the CAT-like activity can facilitate the oxygen-consuming glucose oxidation process of GOx, thus promoting the generation of intracellular reactive oxygen species (ROS). Moreover, the GPX-like activity of HPG@hemin-GOx can deplete intracellular glutathione and thus downregulate GPX4 expression. Consequently, HPG@hemin-GOx induces apoptosis and ferroptosis by ROS-mediated damages of nuclear DNA and mitochondria, and GPX4 depletion-induced lipid peroxidation accumulation, resulting in a strong anticancer effect as demonstrated both in vitro and in vivo. This work provides a method for the construction of polymeric nanoreactors with multienzyme activities for ferroptosis–apoptosis synergistic anticancer therapy.