Multistage nanomedicine engineering offers integrated strategies to overcome glioblastoma treatment barriers

Glioblastoma (GBM) is a highly lethal primary brain tumor. Current intravenously administered therapeutics face significant challenges, including the blood-brain barrier (BBB), the heterogeneous tumor microenvironment, and the dense extracellular matrix, preventing effective drug concentrations at the cellular level. Single-function nanomedicines have shown limited clinical efficacy, highlighting an urgent need for integrated, multistage delivery approaches to improve therapeutic outcomes.

This review conceptualized recent advances in engineered nanomedicines for glioblastoma within a three-step delivery framework. It evaluated preclinical efficacy, safety, and translational potential of various approaches. Step 1 focused on strategies for BBB traversal. Step 2 detailed methods for tumor targeting and accumulation. Step 3 explored techniques for on-site activation and synchronized payload release. The review highlighted how multifunctional nanoplatforms can integrate at least two stages for synergistic therapeutic effects.

The review identified a comprehensive array of strategies across three critical delivery stages. For BBB traversal (Step 1), approaches included leveraging endogenous transcytotic pathways, adaptive protein-corona programming, biomimetic nanocarriers, and BBB modulation techniques such as focused ultrasound with microbubbles, photodynamic therapy, and chemotherapeutic permeabilizers. For tumor targeting and accumulation (Step 2), methods encompassed ligand-decorated and cell-mediated carriers, tumor-penetrating peptides, and magnetically guided drug accumulation. For on-site activation (Step 3), the review highlighted endogenous-responsive linkers (sensitive to pH, redox, hypoxia, and protease cues) and Boolean logic-gated nanodevices that synchronize payload release. Exogenous triggers like light, ultrasound, and magnetic fields were also discussed. > Multifunctional nanoplatforms integrating at least two of these stages were shown to achieve synergistic therapeutic effects, addressing the limitations of single-function approaches.