Supramolecular nanofibers with superior anti-angiogenesis and antitumor properties by enzyme-instructed self-assembly (EISA)

Currently, combination therapy has become a popular research topic in cancer therapy. However, the outcome of the current combination therapy strategy does not satisfy the demand for clinical applications because of factors such as their overlapping toxicities, poor drug payload, and inevitable therapy resistance. Supramolecular self-assembly of peptides holds great potential for solving relevant problems and achieving superior therapeutic effects. In this study, we aimed to propose supramolecular self-assemblies based on a combination therapy strategy, consisting of a heptapeptide A7R for the inhibition of angiogenesis, the chemotherapeutic drug HCPT for treating numerous tumors with high efficacy, and an efficient self-assembling molecular FFY to improve drug loading and cell permeability. We regulated the secondary structure of nanomaterials by optimizing the pathways of self-assembly and significantly improved the affinity of A7R peptide to NRP-1. Endothelial tube formation in Matrigel and a tumor mouse model (in vivo) were then performed to demonstrate the superior antitumor effects of our supramolecular self-assemblies both in vitro and in vivo. In summary, this work not only provides a promising platform for the development of effective combination therapy, but also offers a useful strategy to prepare self-assembled nanomaterials with optimized performance.