Genetically Engineered Biomimetic Nanoparticles for Synergistic Activation of Glioma-Associated Macrophages against Glioblastoma

Glioma-associated macrophages (GAMs) are central mediators of immune evasion and therapeutic resistance in glioblastoma multiforme (GBM) due to their tumor-promoting M2 phenotype and loss of phagocytic activity toward tumor cells. Activating GAMs represent an attractive therapeutic strategy against GBM, but it is hindered by the lack of effective therapies and insufficient drug exposure. Herein, an engineered biomimetic delivery system (SIRPα@BSA/PTX) is developed by enveloping albumin-bound paclitaxel (BSA/PTX) with a genetically engineered melanoma cell membrane expressing SIRPα variants to activate GAMs for improved GBM therapy. SIRPα@BSA/PTX efficiently penetrates the blood-brain barrier (BBB) to accumulate in GBM by leveraging the brain tropism of the melanoma cell membrane. Subsequently, SIRPα variants on the cell membrane, along with PTX in the inner core, synergistically enhance the repolarization and phagocytic abilities of GAMs. <i>In vivo</i> studies show that SIRPα@BSA/PTX significantly suppresses tumor growth and recurrence in orthotopic and postoperative murine GBM models and achieves 100% mouse survival when combined with immune checkpoint inhibitors. Transcriptome analysis of clinical GBM patient samples treated with SIRPα@BSA/PTX also reveals remarkable immune activation signatures, suggesting the great potential of nanoenabled macrophage-based immunotherapy for brain tumors.