Microglial Membrane Camouflaged Nano‐AUTAC to Promote Autophagy‐Mediated β‐Catenin Degradation for Reducing TMZ Resistance in Glioblastoma

ABSTRACT Clinical treatment of temozolomide (TMZ)‐resistant glioblastoma (GBM) remains a significant challenge. This study aims to develop a multifunctional biomimetic Nano‐AUTAC (BM@pPPD/TMZ) that can selectively degrade β‐catenin via autophagy, thereby overcoming TMZ resistance in GBM. BM@pPPD/TMZ is capable of penetrating the blood‐brain barrier (BBB), targeting GBM lesions via microglia‐derived membrane camouflage, and inducing degradation of β‐catenin through the autophagy‐lysosomal pathway. For improving the selective and efficient degradation of β‐catenin, BM@pPPD/TMZ is functionalized with a tri‐functional peptide comprising a β‐catenin‐binding domain, a cathepsin B (CTSB)‐cleavable GLFG linker, and a phosphatidylserine (PS)‐targeting motif. In the GBM microenvironment, the elevated CTSB triggers linker cleavage, promoting membrane shedding and enhancing the cellular uptake. Meanwhile, the incorporation of the cationic lipid DOTAP promotes autophagosome formation, further facilitating degradation of β‐catenin. Both in vitro and in vivo studies demonstrate that BM@pPPD/TMZ is able to effectively penetrate the BBB and accumulate within tumor lesion, concurrently promoting β‐catenin degradation and MGMT downregulation. This finding provides a promising nanotherapeutic strategy for overcoming TMZ resistance and improving GBM therapeutic efficacy.