Biomimetic Hybrid PROTAC Nanovesicles Block Multiple DNA Repair Pathways to Overcome Temozolomide Resistance Against Orthotopic Glioblastoma

Abstract Glioblastoma (GBM) remains one of the deadliest forms of cancer due to its high rates of postoperative recurrence and resistance to treatment. Temozolomide (TMZ) is the standard chemotherapy for GBM. However, the therapeutic efficacy of TMZ is significantly compromised by the activation of various intracellular DNA repair mechanisms that facilitate TMZ resistance. Herein, the upregulation of bromodomain‐containing protein 4 (BRD4) expression is demonstrated to be a key contributor to TMZ resistance in GBM. To address this challenge, a biomimetic hybrid PROteolysis TArgeting Chimeras (PROTAC) liposome delivery system (M@TP) is developed. This system efficiently penetrates the blood‐brain barrier (BBB) and specifically targets GBM cells through homotypic recognition. Once within TMZ‐resistant GBM cells, the released PROTAC from M@TP can specifically degrade BRD4, effectively inhibiting multiple DNA repair pathways and restoring sensitivity to TMZ treatment. In vivo, studies showed that M@TP demonstrated significant efficacy in suppressing tumor growth in both TMZ‐resistant and postoperative GBM, with prolonged mouse survival times. These findings highlight the potential of M@TP as a promising strategy to overcome TMZ resistance and improve therapeutic outcomes in GBM.