Multistage nanomedicine engineering to overcome sequential barriers to glioblastoma treatment: a review

Glioblastoma (GBM) is one of the most lethal primary brain tumors in adults. Intravenously administered therapeutics must cross successive barriers, such as the blood-brain barrier (BBB), heterogeneous tumor microenvironment, and dense extracellular matrix, before achieving pharmacologically relevant concentrations at the cellular level. Nanomedicines with a single function (e.g., BBB penetration) have consistently shown limited efficacy in clinical trials, and thus, elevated the need for an integrated multistage delivery paradigm. This review conceptualized recent advances in engineered nanomedicines for glioblastoma within a three-step delivery framework. Specifically, step 1 involved BBB traversal: endogenous transcytotic pathways, adaptive protein-corona programming, biomimetic nanocarriers, and BBB modulation techniques (e.g., focused ultrasound with microbubbles, photodynamic therapy, and chemotherapeutic permeabilizers). Step 2 involved tumor targeting and accumulation: ligand-decorated and cell-mediated carriers, tumor-penetrating peptides, and magnetically guided drug accumulation. Step 3 involved on-site activation: endogenous-responsive linkers (pH, redox, hypoxia, and protease) and Boolean logic-gated nanodevices that synchronize payload release with spatiotemporal tumor-microenvironment cues, as well as exogenous triggers (e.g., light, ultrasound, and magnetic fields). This review evaluates the preclinical efficacy, safety, and translational potential of the approaches, highlighting how multifunctional nanoplatforms can integrate at least two stages to achieve synergistic therapeutic effects. While clinical trials exhibit promising pharmacokinetics, significant hurdles remain regarding manufacturing, regulatory approval, and immunogenicity, which involves immune recognition and the rapid clearance of nanocarriers. For these reasons, this review outlines strategies to overcome GBM barriers and suggests that multistage integration is essential for developing effective, next-generation precision nanotherapies.