Mitochondria-Targeted Lonidamine Hydrogels for Postsurgical Elimination of Glioblastoma.

The high recurrence rate of glioblastoma after surgical resection and conventional chemotherapy remains a major obstacle to effective treatment. Mitochondria-targeted long-acting local chemotherapy represents a promising therapeutic strategy to tackle this dilemma. In this study, a mitochondria-penetrating peptide (mito) was conjugated with lonidamine (LND), a mitochondrial hexokinase II inhibitor, to construct an amphiphilic peptide-drug conjugate (LND-mito) that could self-assemble into supramolecular hydrogels. This design achieves sustained localized release and mitochondria-targeted delivery, generating a tumor-selective oxidative phosphorylation inhibitor with 19-fold higher potency than LND. Our results demonstrated that LND-mito efficiently targeted tumor cell mitochondria, induced robust reactive oxygen species generation, decreased mitochondrial membrane potential, and activated mitochondrial apoptosis, ultimately markedly inhibiting glioma growth and prolonging postoperative survival in orthotopic glioma-bearing mice. Collectively, this study offers a promising therapeutic strategy for glioma management, while simultaneously informing the design of high-efficacy, low-toxicity local sustained-release delivery platforms for malignant tumors.