Enhancement of Microglia Functions by Developed Nano-Immuno-Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment

Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy has been explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia “restorer”) and D PPA-1 peptide (immune checkpoint blockade) were integrated on a nano-immuno-synergist ( D PAM@OA) to work coordinately. The self-assembled OA core was coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide was attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promoted the recruitment and activation of effector T cells by inhibiting aberrant activation of STAT-3 pathway in microglia, and assisted activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hindered malignant glioma progression and recurrence with or without temozolomide. Our work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors. This article is protected by copyright. All rights reserved

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