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.