Abstract

The immune response rates of patients with glioblastoma (GBM) are relatively low for the complex immunosuppressive tumor microenvironment, which is mainly attributed to the presence of M2-type tumor-associated macrophages (TAMs). Herein, to enhance anti-GBM immune response, we designed a novel biomimetic cascade nanoreactor (Mam@NPs) with “double-punch” strategy for reshaping M2-type TAMs into M1-type. The Mam@NPs were fabricated by encapsulating the CDM-PEG-PDPA diblock copolymer loading imipramine (IM) and aCD47 with macrophage membrane (Mam), which exhibited stepwise pH-responsive characteristics, effective GBM targeting and good antitumor ability. This biomimetic cascade-nanoreactor significantly ablated the tumor cells directly by releasing IM and simultaneously bolstering the anti-GBM effects of aCD47. This augmentation arose from the synergistic remodeling effect of IM and aCD47 on the immunosuppressive tumor microenvironment by enhancing CCL3 secretion, reshaping M2-type TAMs into M1-type, promoting the maturation of dendritic cells, stimulating the proliferation/activation of CD8⁺ T cells, and reducing regulatory T cells. Therefore, this work generates a safe and effective “double-punch” biomimetic cascade-nanoreactor, offering an innovative combination treatment strategy for aCD47 together with IM in GBM immunotherapy.