Adrenomedullin Antagonist Nanoparticles Inhibit Breast Cancer Brain Metastasis by Immunomodulating Monocytes/Macrophages

Breast cancer brain metastasis (BCBM) is a devastating disease with limited treatment options, largely due to the presence of the blood–brain barrier (BBB) in the central nervous system (CNS), and thus, the development of effective alternative therapies for BCBM remains a significant unmet clinical challenge. Herein, we found that monocytes, M2 macrophages, and adrenomedullin (AM) were abundantly present in human BCBM. Therefore, we innovatively proposed monocytes/macrophages as promising immunomodulatory targets for effective immunotherapy of BCBM in mice models. The high-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) nanoparticle efficiently targets monocytes/macrophages. Meanwhile, the adrenomedullin antagonist (AMA)-carrying HPPS (AMA-HPPS) nanoparticle has the potential to target and immunomodulate monocytes/macrophages into antitumor effector cells due to the pro-inflammatory polarization ability of AMA. Given this, AMA-HPPS effectively targeted and modulated circulating monocytes after intravenous injection, enabling the delivery of nanoparticle to brain metastasis sites. Incorporating immunomodulatory CpG into AMA-HPPS (forming AMA-HPPS-CpG) further enhanced monocyte targeting and immunomodulation. Thus, AMA-HPPS-CpG further inhibited the BCBM and prolonged the survival of mice by modulating the differentiation of infiltrating monocytes/macrophages into M1 macrophages and promoting the infiltration of CD8 + T cells into the brain. This effect was attributed to the activation of the NF-κB pathway in monocytes/macrophages following the uptake of nanoparticles, which reprogrammed the immunosuppressive tumor microenvironment. Therefore, this study highlights a promising immunotherapy strategy for brain metastasis by AMA-HPPS nanodrugs eliciting the pro-inflammatory polarization of monocytes/macrophages that have infiltrated the CNS as effector cells rather than considering monocytes/macrophages merely as a drug delivery system across the BBB.