A multifunctional injectable MPDA@MTIC-Co hydrogel platform for synergistic chemotherapy-photothermal therapy of postoperative glioblastoma.

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults, with inevitable postoperative recurrence due to incomplete resection and limited chemotherapy efficacy. Temozolomide (TMZ), the first-line therapy, is hindered by rapid degradation of its active metabolite 3-methyl-(triazene-1-yl)-imidazole-4-carboxamide (MTIC), systemic toxicity, and frequent resistance driven by DNA repair. These shortcomings underscore the urgent need for localized strategies to achieve sustained stability and improve therapeutic outcomes. To address these limitations, we have developed an injectable extracellular matrix-mimicking hydrogel incorporating mesoporous polydopamine nanoparticles loaded with cobalt-stabilized MTIC complexes (MPDA@MTIC-Co). This hydrogel provides mechanical robustness, prolonged intratumoral retention, and sustained on-demand release, while enabling efficient cellular uptake, robust near-infrared-triggered photothermal conversion, and induction of apoptosis through PI3K/AKT pathway suppression. In orthotopic postoperative GBM models, local MPDA@MTIC-Co administration achieves synergistic chemo-photothermal therapy, markedly suppressed recurrence, prolonged survival, and demonstrated excellent biosafety. Collectively, this work establishes a materials-driven localized platform that remodels the postsurgical tumor microenvironment, overcomes the intrinsic limitations of TMZ, and provides a promising strategy for improving patient outcomes in GBM.