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.