A Supramolecular Nanoscavengers: Based "Cargo-Exchange" Breaking Cholesterol Metabolic Dysregulation for Glioblastoma Therapy

Dysregulated Cholesterol metabolism, driven by a complex array of mechanisms, is a defining characteristic of glioblastoma (GBM) and plays a crucial role in the development of resistance to therapeutic interventions. In this study, supramolecular nanoscavengers are engineered by harnessing the intrinsic binding affinity between endogenous small-molecule Cholesterol and β-cyclodextrin (β-CD). This host-guest interaction enabled both targeted drug release and Cholesterol clearance through competitive displacement within the cholesterol-rich microenvironment of GBM. Consequently, tumor-associated Cholesterol dysregulation is effectively disrupted, resulting in significant inhibition of cellular proliferation and invasion. Furthermore, the supramolecular nanoscavengers interfered with the metabolic crosstalk between tumor cells and immune cells involving Cholesterol, thereby remodeling the immunosuppressive tumor microenvironment and demonstrating substantial therapeutic efficacy in vivo. Additionally, the dynamic and reversible binding between β-CD and various guest molecules facilitated efficient delivery of the supramolecular host to the central nervous system (CNS). Collectively, these findings presented a promising strategy for targeting Cholesterol as an intervention in the treatment of GBM as well as Other CNS disorders associated with altered Cholesterol metabolism.

blood‐brain barrier; cholesterol metabolic dysregulation; glioblastoma; host‐guest recognition; immunosuppressive tumor microenvironment; supramolecule.