Surface-engineered dual drug-loaded tumor-targeted liposomal nanoparticles to overcome the therapeutic resistance in glioblastoma multiforme.

BACKGROUND: Glioblastoma (GBM) is the most common high-grade primary malignant brain tumor, characterized by a notably poor prognosis. Current treatments for GBM have shown limited effectiveness in improving patient survival, highlighting the urgent need for novel therapeutic strategies. Combination therapy offers significant potential in overcoming resistance by targeting multiple signaling pathways; however, it often comes with increased toxicity compared to monotherapy. METHODS: We utilized a tumor-targeted liposomal nanoformulation (TTL) and loaded it with everolimus (TTL-E), vinorelbine (TTL-V), rapamycin (TTL-R), a combination (TTL-EV), or (TTL-RV). These formulations were tested in vivo on orthotopic GBM mice, combined with temozolomide and radiation. RNA sequencing was performed to identify molecular and transcriptome changes post-treatment. RESULTS: TTL demonstrated tumor-specific uptake, effectively delivering drugs to GBM tumors. Radiation combined with TTL-EV/RV improved tumor growth inhibition and survival. Transcriptome analysis revealed differentially expressed genes (DEGs) and pathways associated with immune response, DNA damage repair, cell cycle, metabolism, and extracellular matrix pathways. CONCLUSION: TTL crossed the blood-brain barrier, effectively targeting tumors. Radiation plus TTL-EV/RV enhanced tumor suppression and survival in GBM models. Mechanistic studies suggest TTL-EV plus radiation inhibits immune and DNA damage pathways and sensitizes tumors to radiation. These findings offer a potential approach for improving GBM treatment.