<p>Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by rapid progression, high invasiveness, and resistance to conventional therapies. Despite decades of research, effective treatment remains elusive due to the complex molecular landscape of GBM and the formidable challenge posed by the blood–brain barrier (BBB), which significantly restricts the delivery of therapeutic agents to the central nervous system (CNS). This article provides a comprehensive overview of the current understanding of GBM, focusing on the key oncogenic pathways involved in its pathogenesis, including the PI3K/AKT/mTOR, PD-L1 Evasion and signaling cascades. It also highlights the limitations of traditional drug delivery methods in crossing the BBB and explores the potential of advanced nanocarrier systems such as liposomes, polymeric nanoparticles, dendrimers, and exosomes—in overcoming these barriers to enhance drug bioavailability and therapeutic efficacy. We further examine recent advancements in preclinical and clinical trials involving nanomedicine-based GBM treatments, along with notable patent filings that reflect the growing innovation in this field. Finally, we discuss future directions in personalized medicine, combination therapies, and emerging technologies aimed at improving treatment outcomes for GBM patients. Through a multidisciplinary lens, this article underscores the urgent need for novel strategies to address the unmet clinical challenges in glioblastoma therapy.</p>