Gold Nanoparticles Induce Tumor Vessel Normalization and Impair Metastasis by Inhibiting Endothelial Smad2/3 Signaling

Gold nanoparticles (AuNPs) are a promising nanomaterial due to their drug-delivery properties and inherent anti-neoplastic activity. Here, we focused on the anti-neoplastic effects of an improved targeting polymer and folic acid-modified gold nanoparticles (AuNPP-FA) without therapeutic drugs. AuNPP-FA inhibited tumor proliferation both in vitro and in vivo, and tumor metastasis was controlled in vivo. We also found that, in addition to inhibiting tumor angiogenesis, AuNPP-FA normalized tumor vasculature by increasing pericyte coverage and strengthening tight junctions by upregulating VE-cadherin (VE-cad) levels on endothelial cells. This decreased vascular permeability, improved vascular perfusion, and alleviated tissue hypoxia. The immunotherapeutic response was enhanced due to the increased infiltration of CD3⁺CD8⁺ T lymphocytes. AuNPP-FA increased the expression and secretion of semaphorin 3A (SEMA3A) in cancer cells to further inhibit Smad2/3 signaling in human umbilical vein endothelial cells (HUVECs). This normalized tumor vasculature and inhibited metastasis. In conclusion, AuNPP-FA normalized tumor vasculature; therefore, AuNPP-FA has great potential for future clinical applications.