DNA-Free Guanosine-Based Polymer Nanoreactors with Multienzyme Activities for Ferroptosis–Apoptosis Combined Antitumor Therapy

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 (H₂O₂) 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 H₂O₂. 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.