Double-punch strategy: Macrophage membrane-enveloped imipramine and aCD47 reprograms tumor microenvironment to enhance glioblastoma immunotherapy

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.