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

in Journal of controlled release : official journal of the Controlled Release Society by Sufen Li, Jingyan Zhang, Tong Yu, Guangtao Song, Jia Ke, Kai Wang, Yichong Xu, Yiling Hong, Tingting Meng, Yun Hong, Hong Yuan, Fuqiang Hu

TLDR

  • A novel prodrug micelle, CSSOssMIT@MM-PEP, was designed to enhance immunotherapy against glioblastoma by modulating phagocytosis of GBM cells by GAMs.

Abstract

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-PEPinto the GBM tissue. CSSOssMIT@MM-PEPdisassembles into MM-PEPand CSSOssMIT through the proton sponge effect in the acidic microenvironment. MM-PEPblocks 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-PEPincreased GAMs-mediated phagocytosis of GBM cells by 5.01-fold and enhanced CD8T 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.

Overview

  • This study focuses on developing a new strategy to enhance immunotherapy against glioblastoma (GBM) by modulating phagocytosis of GBM cells by glioblastoma-associated macrophages and microglia (GAMs).
  • The study introduces a novel prodrug micelle, CSSOssMIT@MM-PEP, which targets the blood-brain tumor barrier and enhances the delivery of therapeutic agents to the GBM tissue.
  • The primary objective is to develop a noninvasive approach to traverse the blood-brain tumor barrier and modulate GAMs phagocytosis to facilitate effective anti-GBM chemo-immunotherapy.

Comparative Analysis & Findings

  • The study showed that CSSOssMIT@MM-PEP increased GAMs-mediated phagocytosis of GBM cells by 5.01-fold and enhanced CD8 T cell infiltration by 8.63-fold in an orthotopic GBM mouse model.
  • The results demonstrated significant GBM inhibition, highlighting the potential of CSSOssMIT@MM-PEP as a novel therapeutic strategy for glioblastoma treatment.
  • The study also highlighted the limited efficacy of anti-CD47 antibodies in glioblastoma treatment due to the blood-brain tumor barrier and insufficient pro-phagocytosis efficacy of CD47 blockade alone.

Implications and Future Directions

  • This study presents a promising noninvasive strategy for enhancing immunotherapy against glioblastoma by modulating phagocytosis of GBM cells by GAMs.
  • Future studies can focus on optimizing the design and formulation of CSSOssMIT@MM-PEP to further enhance its therapeutic efficacy and minimize potential side effects.
  • The study's findings also highlight the importance of addressing the blood-brain tumor barrier and modulating GAMs phagocytosis to achieve effective anti-GBM chemo-immunotherapy.
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