Tumor-Associated Macrophages Nano-Reprogrammers Induce "Gear Effect" to Empower Glioblastoma Immunotherapy.

Glioblastoma (GBM), the most malignant brain tumor with high prevalence, remains highly resistant to the existing immunotherapies due to the significant immunosuppression within tumor microenvironment (TME), predominantly manipulated by M2-phenotypic tumor-associated macrophages (M2-TAMs). Here in this work, an M2-TAMs targeted nano-reprogrammers, MG5-S-IMDQ, is established by decorating the mannose molecule as the targeting moiety as well as the toll-like receptor (TLR) 7/8 agonist, imidazoquinoline (IMDQ) on the dendrimeric nanoscaffold. MG5-S-IMDQ demonstrated an excellent capacity of penetrating the blood-brain barrier (BBB) as well as selectively targeting M2-TAMs in the GBM microenvironment, leading to a phenotype transformation and function restoration of TAMs shown as heightened phagocytic activity toward tumor cells, enhanced cytotoxic effects, and improved tumor antigen cross-presentation capability.