Synergistic tumor microenvironment targeting and blood-brain barrier penetration via a pH-responsive dual-ligand strategy for enhanced breast cancer and brain metastasis therapy

Acid cleavable FA and dNP2 peptide co-modified PTX-loaded liposomes (cFd-Lip/PTX) exhibited synergistic TME targeting and BBB penetration. Firstly, FA ligand mediated the tumor targeting by the interaction between FA and FR on tumor cells. Upon arrival at the TME, FA ligand was cleaved, maximazing the cell permeability of dNP2 peptide, which consequently promoted the internalization of FR-positive tumor cells and FR-negative CAFs. Besides, the FA and dNP2 also promoted the penetration across the BBB synergistically, and therefore enhanced the dual targeting of tumor cells and stromal cells in the brain metastatic site.133