Self-Assembled Peptide Nanoparticle-Mediated Macrophage Polarization Enhances Anticancer Efficacy of Chemotherapeutics in Triple-Negative Breast Cancer

Peptide-based self-assembled materials are being investigated as a biodegradable option with various biomedical applications such as drug-delivery carriers and as biosensors. In this study, we report the mechanism of action of a synthetic β-sheet and turn rich macrocyclic host defense peptide that self-assemble in the form of nanoparticles and stimulate naïve and tumor-associated macrophages, resulting in the production of pro-inflammatory mediators in macrophage monoculture and in a macrophage/triple-negative breast cancer (TNBC) coculture model. Our results show that macrocyclic peptide-based nanomaterials termed as mCA4 engage with toll-like receptors of macrophages, activating downstream pathways in both naïve and IL-4-pretreated macrophages, and result in the production of pro-inflammatory mediators by the immune cells. The immunomodulatory potential of mCA4 is highly sequence-specific, and while an inactive analogue prepared by swapping a single amino acid in the peptide chain does not diminish the self-assembly properties of the parent peptide, its impact on the immunomodulatory potential is detrimental. The immunomodulatory potential of mCA4 is further confirmed in macrophage monoculture and in macrophage/TNBC coculture by proteomics and by Western blot analysis. The treatment of macrophage/TNBC coculture with mCA4 and chemotherapeutics enhanced anticancer efficacies of chemotherapeutics, suggesting immuno-adjuvant-like properties of materials for TNBC treatment.