Suit the Remedy to the Case: An Activatable DNA Damage Initiator for Postsurgical Therapy of Glioblastoma with TP53 Mutations

Glioblastoma (GBM) with TP53 mutations is a typical subtype of intracranial tumors that rapidly recurs. Herein, we demonstrated that PD0166285 (PD), a dual-targeted inhibitor of WEE1 and PKMYT1, specifically activated DNA damage of TP53-mutant GBM cells for inducing a robust apoptotic effect. Suiting the remedy to the case, the injectable double-network hydrogels (DNHs) encapsulating PD were constructed on the basis of acid-sensitive Fe³⁺/tannic acid (TA) metal-phenolic networks (MPNs). Particularly, the incorporation of MPNs not only endowed PD-loaded hydrogels (PDNHs) with on-demand drug delivery but also controllably generated reactive oxygen species (ROS). Furthermore, ROS could amplify DNA damage stress, which demonstrated the potential of PDNHs as an activatable initiator to in situ trigger high-level DNA damage of TP53-mutant GBM cells. Thus, PDNHs remarkably restricted the postsurgical relapse of orthotopic GBM carrying TP53 mutations and improved the survival time of mice. This study presents a valuable strategy for suiting the remedy to postsurgical TP53-mutant GBM.