Sequentially Responsive Three-Lobed Supramolecular Platform for Tumor Microenvironment Remodeling and Blood-Brain Barrier Penetration.

Glioblastoma (GBM) therapy is severely hindered by the inflammatory tumor microenvironment (TME) and insufficient penetration of biological barriers, which lead to poor therapeutic efficacy and severe side effects. Herein, we rationally designed and constructed a novel three-lobed supramolecular delivery platform via π-π stacking and covalent cross-linking, which enables enhanced responsiveness to the inflammatory TME and superior blood-brain barrier penetration for multi-modal synergistic GBM therapy. Notably, this platform exhibits a sequential response to the inflammatory TME characterized by high ROS levels and acidic pH, thereby achieving on-demand drug release, as well as efficient targeted accumulation across biological barriers. Furthermore, it exerts potent synergistic anti-tumor effects through near infrared (NIR) photothermal ablation, chemotherapy, and JAG1/NOTCH1 signaling pathway inhibition, while maintaining excellent in vivo biocompatibility without obvious damage to normal tissues and organs. This multi-module supramolecular assembly strategy provides a gradually progressive approach for precise therapy by anchoring the pathological characteristics, thereby advancing the revolutionary iteration of the GBM treatment system.