Glioblastoma multiforme is the most aggressive brain tumor, due to its high invasiveness and genetic heterogeneity. Moreover, the blood-brain barrier prevents many drugs from reaching a therapeutic concentration at the tumor site, and most of the chemotherapeutics lack in specificity toward cancer cells, accumulating in both healthy and diseased tissues, with severe side effects. Here, we present in vitro investigations on lipid-based nanovectors encapsulating a drug, nutlin-3a, and superparamagnetic iron oxide nanoparticles, to combine the proapoptotic action of the drug and the hyperthermia mediated by superparamagnetic iron oxide nanoparticles stimulated with an alternating magnetic field. The nanovectors are functionalized with the peptide angiopep-2 to induce receptor-mediated transcytosis through the blood-brain barrier and to target a receptor overexpressed by glioma cells. The glioblastoma multiforme targeting efficiency and the blood-brain barrier crossing abilities were tested through in vitro fluidic models, where different human cell lines were placed to mimic the tumor microenvironment. These nanovectors successfully cross the blood-brain barrier model, maintaining their targeting abilities for glioblastoma multiforme with minimal interaction with healthy cells. Moreover, we showed that nanovector-assisted hyperthermia induces a lysosomal membrane permeabilization that not only initiates a caspase-dependent apoptotic pathway, but also enhances the anticancer efficacy of the drug.