Drug-Free Hybrid Nanoarchitecture Modulation of the Metastatic Behavior of Pancreatic Ductal Adenocarcinoma in Alternative in Vivo Models

Metastasis is the key cause of treatment failure in most oncological patients. The spreading of cancer cells to distal tissues and organs can be associated with the epithelial-to-mesenchymal transition (EMT) that reduces or nullifies the effectiveness of the actual treatments. In this context, the establishment of effective antimetastatic agents is the final frontier in cancer research. Noble metal nanomaterials may allow advancements in this regard, but the issue of their persistence precludes their translation to clinics despite their antimetastatic properties. Here, we demonstrate that non-persistent gold and copper ultrasmall-in-nano architectures (NAs) conceived by a safe-by-design approach reduce tumor growth and modulate the progression of the metastasis by altering gene and protein expression of the EMT-related factors in alternative in vivo models of pancreatic ductal adenocarcinoma. Together with these findings, we also introduce an alternative biomodel for the evaluation of metastasis to mimic the heterogeneity of the metastatic phenomenon. On a broader basis, our results represent a promising step forward in the development of novel families of ultrasmall-in-nano antimetastatic agents for the establishment of the next clinical approaches for pancreatic cancer metastasis.