Tumor macrovascular invasion (MVI) frequently occurs in highly metastatic tumors, with high mortality and poor prognosis. Conventional in vitro 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 in vitro model of MVI, offering a powerful tool for evaluating multiple bio-effects of therapeutic agents in advanced cancers.

Safe and non-invasive physical delivery tools for nucleic acids provide new therapeutic options for diseases lacking targets, such as triple-negative breast cancer (TNBC). However, existing electroporation devices rely on high voltages and rigid electrode materials. Here we propose an electronic bra (termed NEO-BRA) capable of noninvasive electroporation for transdermal gene therapy as a neoadjuvant therapy for TNBC. The NEO-BRA integrates intrinsically flexible substrates and liquid metal-polymer conductors, enabling conformal contact with target tissue. High-density, 3D structured conductors resulted in electrotransfection of nucleic acids at the lowest voltage (25 V) among in vivo devices. Human breast model simulations and porcine skin experiments demonstrated that the delivery could reach a depth of 1 mm, supporting real-world application to human patients. Delivery of forkhead box M1 (FOXM1) siRNA by NEO-BRA on mice bearing TNBC tumors showed a significant tumor therapeutic effect, which reduced tumor growth by 2/3, programmed death-ligand 1 (PD-L1) expression by 3/4, and eliminated detectable lung metastasis, without invasiveness or toxicity. The NEO-BRA provides a bioelectronic interface for a novel neoadjuvant therapy of TNBC and other promising wearable tumor therapies.