Cathepsin B-Responsive Programmed Brain Targeted Delivery System for Chemo-Immunotherapy Combination Therapy of Glioblastoma

作者：Shaoping Jiang, Wenpei Li, Jun Yang, Tian Zhang, Yuquan Zhang, Lin Xu, Bo Hu, Zhi Li, Huile Gao, Yuanyu Huang, Shaobo Ruan · 发表于：ACS Nano · 年份：2024 · DOI：10.1021/acsnano.3c11958 · 被引用次数：57 · 研究领域：Extracellular vesicles in disease、Nanoplatforms for cancer theranostics、Immune cells in cancer

Tumor-associated macrophages (TAMs) are closely related to the progression of glioblastoma multiform (GBM) and its development of therapeutic resistance to conventional chemotherapy. TAM-targeted therapy combined with conventional chemotherapy has emerged as a promising strategy to combat GBM. However, the presence of the blood–brain barrier (BBB) severely limits the therapeutic efficacy. Meanwhile, the lack of ability to distinguish different targeted cells also poses a challenge for precise therapy. Herein, we propose a cathepsin B (CTSB)-responsive programmed brain-targeted delivery system (D&R-HM-MCA) for simultaneous TAM-targeted and GBM-targeted delivery. D&R-HM-MCA could cross the BBB via low density lipoprotein receptor-associated protein 1 (LRP1)-mediated transcytosis. Upon reaching the GBM site, the outer angiopep-2 modification could be detached from D&R-HM-MCA via cleavage of the CTSB-responsive peptide, which could circumvent abluminal LRP1-mediated efflux. The exposed p -aminophenyl-α- d -mannopyranoside (MAN) modification could further recognize glucose transporter-1 (GLUT1) on GBM and macrophage mannose receptor (MMR) on TAMs. D&R-HM-MCA could achieve chemotherapeutic killing of GBM and simultaneously induce TAM polarization from anti-inflammatory M2 phenotype to pro-inflammatory M1 phenotype, thus resensitizing the chemotherapeutic response and improving anti-GBM immune response. This CTSB-responsive brain-targeted delivery system not only can improve brain d...