Targeting the undruggable in glioblastoma using nano-based intracellular drug delivery.

Glioblastoma (GBM) is a highly prevalent and aggressive brain tumor in adults with limited treatment response, leading to a 5-year survival rate of less than 5%. Standard therapies, including surgery, radiation, and chemotherapy, often fall short due to the tumor's location, hypoxic conditions, and the challenge of complete removal. Moreover, brain metastases from cancers such as breast and melanoma carry similarly poor prognoses. Recent advancements in nanomedicine offer promising solutions for targeted GBM therapies, with nanoparticles (NPs) capable of delivering chemotherapy drugs or radiation sensitizers across the blood-brain barrier (BBB) to specific tumor sites. Leveraging the enhanced permeability and retention effect, NPs can preferentially accumulate in tumor tissues, where compromised BBB regions enhance delivery efficiency. By modifying NP characteristics such as size, shape, and surface charge, researchers have improved circulation times and cellular uptake, enhancing therapeutic efficacy. Recent studies show that combining photothermal therapy with magnetic hyperthermia using AuNPs and magnetic NPs induces ROS-dependent apoptosis and immunogenic cell death providing dual-targeted, immune-activating approaches. This review discusses the latest NP-based drug delivery strategies, including gene therapy, receptor-mediated transport, and multi-modal approaches like photothermal-magnetic hyperthermia combinations, all aimed at optimizing therapeutic outcomes for GBM.