Tertiary amine modification enables triterpene nanoparticles to target the mitochondria and treat glioblastoma via pyroptosis induction

Abstract

Glioblastoma (GBM), the most common primary brain tumor, lacks effective treatments. Emerging evidence suggests mitochondria as a promising therapeutic target, albeit successfully targeting represents a major challenge. Recently, we discovered a group of triterpenes that can self-assemble into nanoparticles (NPs) for cancer treatment. However, unmodified triterpene NPs lack affinity for mitochondria. In this study, using oleanolic acid (OA) as an example, we demonstrated that tertiary amine modification enabled triterpene NPs to selectively target the mitochondria through interaction with translocase of outer mitochondrial membrane 70 (TOM70) leading to effective killing of GBM cells via pyroptosis. We showed that the NPs could be engineered for preferentially penetrating brain tumors through surface conjugation of iRGD, and treatment with the resulting NPs significantly prolonged the survival of tumor-bearing mice. We found that the efficacy could be further improved by encapsulating lonidamine, a mitochondrial hexokinase inhibitor. Furthermore, the observed mitochondria targeting effect through tertiary amine modification could be extended to other triterpenes, including lupeol and glycyrrhetinic acid. Collectively, this study reveals a novel strategy for targeting the mitochondria through tertiary amine modification of triterpenes, offering a promising avenue for the effective treatment of GBM.