Liposome Incorporated Nanodrug Formulation for Inhibiting Glioblastoma by Inducing Mitochondria Dysfunction and Autophagy

Glioblastoma multiforme (GBM) has the highest mortality rate in the central nervous system and currently has no effective treatment. G protein-coupled estrogen receptor 1 (GPER1) is involved in several cancers, such as esophageal carcinoma and glioblastoma. G-1, a GPER1 agonist, has a strong antitumor effect on glioblastoma. However, the specific mechanisms are yet to be studied and verified. Liposomes can be better absorbed using a passive targeting strategy based on the EPR effect, which are potential drug delivery candidates and are effective in penetrating through the blood-brain barrier (BBB). In this study, we showed a significant improvement in the antitumor therapy efficacy for glioma through liposome-modified G-1 (Lpo@G-1 nanoparticles [NPs]), which delivers drugs through the BBB. The resulting formulation, Lpo@G-1 NPs, displays excellent colloidal stability together with a high encapsulation efficiency (EE ≈ 88.5%) and drug-loading content (LC ≈ 31.6%). The antitumor activity of G-1, a small molecule, and Lpo@G-1 NPs against GBM was evaluated while exploring its underlying mechanisms. G-1 significantly inhibits GBM cell proliferation and reduces the migration and invasion of GL261 mouse glioma cell lines and U251 human glioma cell lines. Moreover, G-1 induced mitochondrial dysfunction and autophagy. Differential gene enrichment analysis and pathway validation revealed that G-1 exerted its anti-GBM effects through lipid peroxidation and ferroptosis, leading to a marked reduction in tumorigenicity. These findings suggest that Lpo@G-1 NPs are promising therapeutic candidates for the effective and safe treatment of GBM.