Legumain Protease-Activated Tuftsin-Functionalized Nanoparticles For Dual-Targeting Tams And Cancer Chemotherapy

M2 tumor-associated macrophages (TAMs) play a pivotal role in cancer progression and therapy resistance. Inhibition of TAMs is of great significance to reshape the protumor environment to benefit therapeutic outcomes. In this work, we developed a novel TAMs and tumor cells dual-targeting nanoparticle (AT(pep)-NPs) system for cancer chemotherapy by integrating a docetaxel (DTX)-loaded nanocarrier and a multi-function peptide AT(pep), which is composed of a phagocytosis-stimulating peptide-tuftsin (T-pep) fused with a substrate peptide-alaninealanine-asparagine (AAN) of endoprotease legumain. In vitro protelytic and cellular uptake assays confirmed AT(pep)-NPs can be responsively activated into T-pep-NPs by cleavage of legumain that is overexpressed in both tumor cells and TAMs, which then promoted tumor cells internalization and TAMs phagocytosis through neuropilin-1/Fc receptor pathways. Due to AAN deactivation effect, AT(pep)-NPs can effectively decrease the T-pep-induced non-specific uptake by M1-polarized and normal macrophage during systemic circulation. Our results of in vivo experiments demonstrated AT(pep)-NPs outperformed T-pep-NPs in tumor and TAMs dual-targeting delivery efficiency with markedly enhanced efficacy against both tumor growth inhibition and TAMs depletion. Overall, this study offers a novel approach for development of multitargeted delivery vehicle for improved cancer chemotherapy.