A Supramolecular Nanoscavengers: based "Cargo-Exchange" Breaking Cholesterol Metabolic Dysregulation for Glioblastoma Therapy
Time：2025/11/26 21:56:40 Views：147
Glioblastoma is a common primary malignant brain tumor, the efficacy of these therapeutic modalities is constrained by several factors, including intricate signaling pathways, intratumoral genetic diversity, the blood-brain barrier (BBB), and an immunosuppressive tumor microenvironment. In this study, leveraging the distinct characteristics of cholesterol—a key endogenous lipid molecule—in the central nervous system and its inherent affinity for β-cyclodextrin (β-CD), we constructed an in-situ triggerable "guest-exchange" nanoscavengers. The associated findings were published in the international authoritative journal Advanced Science under the title” A Supramolecular Nanoscavengers: based "Cargo-Exchange" Breaking Cholesterol Metabolic Dysregulation for Glioblastoma Therapy”.
In the processes of tumorigenesis and tumor progression, cancer cells engage in continuous metabolic adaptation to optimally respond to their changing environment. Notably, GBM exhibits a prominent characteristic of lipid metabolism reprogramming. It is important to highlight that cholesterol—a crucial lipid molecule for maintaining the structure and function of the CNS-is subject to limited or negligible transport from peripheral circulation into the CNS due to stringent restrictions imposed by the BBB. Recently, supramolecular nanomaterials have garnered significant attention as they serve dual roles as both drug carriers and therapeutic agents. β-CD demonstrates notable therapeutic potential. The cavity of β-CD exhibits a high degree of structural compatibility with the steroid nucleus of cholesterol, a crucial lipid molecule that is widely distributed throughout biological systems. Consequently, it can form a stable complex with cholesterol, thereby facilitating its clearance from the body. However, several challenges associated with β-CD, including limited water solubility, inability to effectively penetrate the BBB and and non-specific distribution patterns have severely limited its application in CNS diseases. Therefore, it is imperative to modify the structure of β-CD through chemical modification to safely, effectively and precisely transport it to the CNS to regulate cholesterol metabolism disorders and treat GBM.
In light of the cholesterol metabolic reprogramming and the stringent BBB characteristics exhibited by GBM, this research exploited the natural affinity between β-CD and cholesterol to construct a supramolecular nanoscavengers grounded on the “cargo-exchange” mechanisms. Moreover, this supramolecular nanoscavengers was modified with ApoE polypeptide, endowing it with the ability to bind to the LDLR receptors that are highly expressed in the BBB and tumor cells. In the cholesterol-enriched tumor microenvironment, given that the natural affinity between cholesterol and β-CD surpasses that between β-CD and avasimibe (AVA), through host-guest recognition-exchange interactions, the drug molecule AVA was liberated to fulfill its function of inhibiting the cholesterol esterification process. Simultaneously, β-CD performed the dual functions of a carrier-scavenger. Within the tumor microenvironment, β-CD further bound to cholesterol, thereby forming a cholesterol-CD complex. This binding behavior was instrumental in scavenging excess cholesterol, which in turn contributed to reducing CD8+ T cell exhaustion, inhibiting the infiltration of inhibitory macrophages and regulatory T cells, and finally remodeling the immunosuppressive microenvironment.
Tian Zonghua, a doctoral candidate in the research group, serves as the first author of the paper. Professor Chen Jiang is the corresponding author, with Associate Professor Tao Sun as the co-corresponding author. This research was supported by the National Natural Science Foundation of China, the Shanghai Science and Technology Major Program, the Open Research Fund of Pingyuan Laboratory, and Zhangjiang Laboratory.
Original link: https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202519690
