Postoperative Injection of a Triptolide‐Preloaded Hydrogel Prevents the Recurrence of Glioblastoma by Dual‐Pathway Activation of Ferroptosis

Glioblastoma (GBM) recurrence leads to high mortality, which remains a major concern in clinical therapy. Herein, an injectable triptolide (TP)‐preloaded hydrogel (TP@DNH) accompanied by a postoperative injection strategy is developed to prevent the recurrence of GBM. With a potential inhibitor of the NRF2/SLC7A11/GPX4 axis, it is demonstrated that TP can deactivate glutathione peroxidase 4 (GPX4) from the source of glutathione (GSH) biosynthesis, thereby activating ferroptosis in GBM cells by blocking the neutralization of intracellular lipid peroxide (LPO). Based on acid‐sensitive Fe3+/tannic acid (TA) metal‐phenolic networks (MPNs), the TP@DNH hydrogel can induce the effective generation of reactive oxygen species (ROS) through Fe3+/TA‐mediated Fenton reaction and achieve controllable release of TP in resected GBM cavity. Due to ROS generation and GPX4 deactivation, postoperative injection of TP@DNH can achieve high‐level ferroptosis through dual‐pathway LPO accumulation, remarkably suppressing the growth of recurrent GBM and prolonging the overall survival in orthotopic GBM relapse mouse model. This work provides an alternative paradigm for regulating ferroptosis in the postoperative treatment of GBM. Herein, a triptolide (TP)‐preloaded double‐network hydrogel (TP@DNH) is designed to prevent the recurrence of glioblastoma (GBM) by postoperative in situ injection. By introducing acid‐sensitive MPNs, TP@DNH evokes Fe3+‐mediated Fenton reaction and inhibits the NRF2/SLC7A11 axis by TP in response to acidic tumor microenvironment. Accordingly, TP@DNH‐ induced dual‐pathway lipid hydroperoxide accumulation achieves high‐level ferroptosis in the residual GBM cells.