Microglia membrane-mediated trans-blood-brain barrier prodrug micelles enhance phagocytosis for glioblastoma chemo-immunotherapy.

Glioblastoma-associated macrophages & microglia (GAMs) are critical immune cells within the glioblastoma (GBM) microenvironment. Their phagocytosis of GBM cells is crucial for initiating both innate and adaptive immune responses. GBM cells evade this immune attack by upregulating the anti-phagocytic molecule CD47 on their surface. Although CD47 knockdown has shown promise in reducing tumor volume and increasing survival in GBM models, the efficacy of anti-CD47 antibodies remains limited clinically, partly due to the blood-brain tumor barrier (BBTB) and the insufficient pro-phagocytosis efficacy of CD47 blockade alone. Here, we introduce CSSOssMIT@MM-PEP, a PEP-linked microglia membrane (MM) camouflaged CSSOssMIT prodrug micelle. The MM targets vascular cell adhesion molecule-1 on the BBTB and enhances the penetration of CSSOssMIT@MM-PEP into the GBM tissue. CSSOssMIT@MM-PEP disassembles into MM-PEP and CSSOssMIT through the proton sponge effect in the acidic microenvironment. MM-PEP blocks the CD47-SIRPα axis, disabling the 'don't eat me' signal, while CSSOssMIT releases MIT within tumor cells to promote immunogenic cell death and amplify the 'eat me' signal. In an orthotopic GBM mouse model, CSSOssMIT@MM-PEP increased GAMs-mediated phagocytosis of GBM cells by 5.01-fold and enhanced CD8 T cell infiltration by 8.63-fold, demonstrating significant GBM inhibition. Overall, this study presents a noninvasive strategy to traverse the BBTB and modulate GAMs phagocytosis, thereby facilitating effective anti-GBM chemo-immunotherapy.