Next-Generation Liposomal and Nanoparticle-Based Systems for Glioblastoma: Molecular Targeting Strategies to Overcome the Blood–Brain Barrier

Glioblastoma (GBM) remains one of the most lethal and intractable central nervous system malignancies, characterized by aggressive cellular proliferation, profound hypoxia, and an immunosuppressive microenvironment. The primary pharmacokinetic obstacle for systemic interventions is the blood–brain barrier (BBB), which restricts the infiltration of free therapeutic agents. To overcome this limitation, translational nanomedicine has driven the design of next-generation delivery systems, including liposomal vectors and synthetic organic, inorganic, and hybrid nanoparticles. This study establishes an exhaustive analysis of molecular targeting strategies designed to actively hijack physiological transport pathways via receptor-mediated transcytosis (RMT) targeting transferrin, lactoferrin, and LRP1 receptors and adsorption-mediated transcytosis (AMT) using polycationic biomaterials. Terminal selectivity via tumor-specific antigens, such as EGFRvIII and nucleolin (targeted by the AS1411 aptamer), is also discussed alongside smart stimuli-responsive platforms that exploit the tumor microenvironment’s acidic pH, hypoxia, and matrix metalloproteinase activity for localized drug release. Concurrently, the deployment of these nanoplatforms for the intracellular vectorization of advanced genetic material, including siRNA (targeting VEGF and MGMT) and CRISPR/Cas9 complexes, demonstrates significant efficacy in reversing genomic chemoresistance and collapsing tumor neoangiogenesis. Finally, the review addresses critical bioengineering and clinical bottlenecks such as manufacturing scale-up, human BBB complexity, opsonization, and the long-term toxicity of inorganic nanoparticles that currently limit the regulatory transition of these highly promising neuro-oncological nanotechnologies from bench to bedside.