Overcoming standard-of-care resistance in glioblastoma using nanoparticle-based drug delivery targeting the autophagy pathway.

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by rapid growth, diffuse infiltration, and a dismal prognosis. Despite aggressive treatment involving maximal surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy, therapeutic outcomes remain poor due to intrinsic and acquired resistance. Autophagy, a catabolic process that degrades damaged cellular components, plays a critical role in this resistance by enabling tumor cells to survive under metabolic, hypoxic, and therapeutic stress conditions. Notably, modulation of autophagy has emerged as a promising avenue to overcome drug resistance. Recent advances in nanomedicine offer innovative strategies to enhance drug delivery and therapeutic efficacy. Nanoparticle-based drug delivery systems (NDDS) improve the bioavailability of drug molecules, facilitate blood-brain barrier (BBB) penetration, and enable targeted delivery to tumor tissues. This review explores the synergistic potential of integrating NDDS with autophagy-targeting strategies to treat GBM. Various nanoparticle platforms-including liposomes, dendrimers, polymeric nanoparticles, and lipid-based carriers-are highlighted for their ability to modulate autophagy and deliver anti-cancer agents effectively. Furthermore, we discuss the dual role of autophagy in GBM progression and the importance of context- and time-specific modulation. Thus, combining autophagy inhibitors or modulators with nanoparticle-based systems and standard therapies holds promise as a novel therapeutic strategy to counteract resistance and improve patient survival in GBM.