Next Generation of Brain Cancer Nanomedicines to Overcome the Blood-Brain Barrier (BBB): Insights on Transcytosis, Perivascular Tumor Growth, and BBB Models

Brain cancers, particularly malignant gliomas such as glioblastoma, are highly invasive and characterized by elevated complexity, heterogeneity, and high infiltration ability. Therefore, they pose a significant challenge to conventional treatments due to the limited drug permeability of the blood-brain barrier (BBB), the involvement of numerous acquired and intrinsic drug resistance mechanisms in metastatic brain tumors, and the high sensitivity of surrounding healthy tissues. Despite recent advances in diagnosis and treatment, their prognosis remains poor, with their median overall survival rarely exceeding 12 months. To overcome these limitations, different nanomedicine-based therapeutic approaches have recently been proposed, aiming to provide more effective and safer drug delivery for targeting brain cancers. However, most reported nanomedicines to date have failed to meet the high expectations in the clinic. This fact can be attributed to limited understanding of brain tumor biology and lack of knowledge about bio-nanoparticle interactions, among other factors. This review discusses recent progress in brain cancer nanomedicines, with a particular focus in understanding intracellular sorting mechanisms, perivascular tumor growth, and the design of advanced BBB models. It also highlights how an improved understanding of brain tumor biology can pave the way for designing safer and more effective nanomedicines for brain cancer treatment. The review presents an overview of nanomedicines in brain-targeted drug delivery, followed by a discussion of challenges impeding the effectiveness of brain cancer nanomedicines. The focus is on highlighting recent advancements in understanding brain cancer biology, including intracellular trafficking at the blood-brain barrier (BBB), perivascular tumor growth, and advanced BBB model design, offering exciting avenues for next-generation brain cancer nanomedicines.image