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 is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia restorer) and DPPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist (DPAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which DPPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, DPAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists 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 hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors. A novel microglia-targeted nano-immuno-synergist (DPAM@OA) carrying OA is devised to bolster microglia's immune function and incorporate DPPA-1 peptide to block PD-L1, effectively impeding the progression and recurrence of malignant glioma. This research highlights the promising therapeutic potential of well-designed nanocarriers in combining microglia repair with specific immunotherapy for brain tumors.image

Automated summary

A novel microglia-targeted nano-immuno-synergist (DPAM@OA) carrying OA is devised to bolster microglia's immune function and incorporate DPPA-1 peptide to block PD-L1, effectively impeding the progression and recurrence of malignant glioma. This research highlights the promising therapeutic potential of well-designed nanocarriers in combining microglia repair with specific immunotherapy for brain tumors.