Fabricating a macrovascular-invaded tumor model using an aerogel scaffold for evaluation of therapeutics

Tumor macrovascular invasion (MVI) frequently occurs in highly metastatic tumors, with high mortality and poor prognosis. Conventional <i>in vitro</i> three-dimensional (3D) models, including organoids and organ-on-a-chip systems, fail to replicate the characteristics of MVI due to their limited sizes and lack of a hemodynamic environment. Here, we fabricate a polymeric aerogel tube (PAT) and load its inner and outer surfaces with endothelial cells and tumor cells to construct the macrovascular invaded tumor model. The large-sized interconnecting porous structure of the PAT allows cell accommodation, growth and migration. Under continuous perfusion culture, the model has a complete endothelial cell layer and tumor cells aggressively grow toward the endothelium to form the structure that tumor tissue wraps around the blood vessel, resulting in dense tumor tissues with a biomimetic extracellular matrix for resembling the tumor macrovascular invasion process. We evaluate the tumor retention and gene transfection efficiency of nanomedicines using this model. Additionally, human immune cells are introduced into this system to enable the investigation of anti-tumor efficacy and immune activation of therapeutics. Altogether, we present the first <i>in vitro</i> model of MVI, offering a powerful tool for evaluating multiple bio-effects of therapeutic agents in advanced cancers.