Surface-Engineered Nanoshuttles Hijack Macrophages In Vivo to Boost Blood–Brain Barrier Penetration and Immunomodulation for Targeted Glioblastoma Therapy

Macrophage-hitchhiking drug delivery across the blood-brain barrier (BBB) has garnered considerable attention for its potential in glioblastoma (GBM) treatment. However, challenges such as the complexity of in vitro synthesis and the risk of macrophage polarization toward protumor phenotypes hinder its practical application. We developed a receptor ligand-free nanoshuttle that can hitchhike on macrophages in vivo for efficient BBB penetration and targeted drug delivery while inducing macrophage polarization toward antitumor phenotypes for GBM therapy. The nanoshuttle was constructed through surface engineering of a Fe-containing metal-organic framework (MOF) to optimize its hydrophilicity and was loaded with ginsenoside Rh2 (Rh2). Upon intravenous injection, the nanoshuttles specifically adsorbed proteins from the complement system, forming a protein corona that enhanced macrophage endocytosis and facilitated the in vivo synthesis of the macrophage-hitchhiking nanoshuttles. Exploiting the chemotaxis of macrophages toward GBM tissue, the macrophage-hitchhiking nanoshuttles efficiently penetrated the BBB and target GBM tissue. The intrinsic iron species of the nanoshuttle regulated iron metabolism in the tumor microenvironment, directing macrophage polarization toward an antitumor M1 phenotype for immunotherapy. Combined with the ^•OH generating capacity of Fe-MOF and the tumor-killing effects of Rh2, these nanoshuttles effectively suppressed tumor growth and improved survival in a GBM mouse model.