Abstract

Highly aggressive tumor cells fulfill their metabolic demands by forming vascular-like channels through a process of cellular deformation and extracellular matrix (ECM) remodeling, known as vasculogenic mimicry (VM). This phenomenon contributes to the limited efficacy of anti-angiogenic therapies and promotes tumor progression, making VM inhibition a promising yet challenging therapeutic strategy. To address this, we developed a biomimetic nanoplatform, termed GDVs@CuPBA-iRGD, through the in-situ mineralization of a copper-based Prussian blue analogue (CuPBA) onto ginseng-derived vesicles (GDVs), followed by conjugation with the tumor-penetrating peptide iRGD. The resulting nanocomposite exhibited excellent pH-responsive degradation, enabling controlled drug release within the tumor microenvironment. In vitro, GDVs@CuPBA-iRGD was efficiently internalized by hepatocellular carcinoma (HCC) cells, significantly suppressing their viability, invasion, and VM formation while simultaneously inducing cuproptosis and ferroptosis. Consistent with these findings, in vivo studies confirmed that GDVs@CuPBA-iRGD exhibits superior accumulation in the liver, resulting in potent inhibition of both VM and tumor progression, all while maintaining high biosafety. Mechanistically, the anti-VM effect is primarily mediated by the nuclear translocation of PPARγ. This key event triggers a transcriptional reprogramming that downregulates critical VM-associated genes, thereby disrupting the ECM remodeling essential for VM. Moreover, single-cell RNA sequencing (scRNA-seq) analysis indicated that VM suppression by GDVs@CuPBA-iRGD triggered the subsequent activation of antitumor immunity. This work highlights a novel bioinspired and synergistic therapeutic strategy for the precise treatment of VM-dependent aggressive tumors. Graphical abstract