Nanostapled Peptide Empowered Tumor Targeting and Programmed Release of a Therapeutic Peptide for Colorectal Cancer Therapy.

Stapled peptides exhibit superior proteolytic stability and cell permeability, relative to linear peptides. However, non-specific tissue distribution precipitates dose-limiting toxicities, constraining the therapeutic implementation. Here, we designed a self-assembling nanostapled peptide (NSP) comprising hydrophilic mPEG1000 groups surrounding a hydrophobic core made up of a therapeutic stapled peptide. In vivo, the nanostructure protected the peptide from non-target tissues, thereby improving bioavailability. Specifically, under the acidic and MMP-9-rich conditions of the tumor microenvironment, the therapeutic peptide could be released through programmed disassembly to penetrate the colorectal cancer cells and activate a downstream apoptotic pathway. Collectively, this study establishes NSP as a promising platform for the precise and effective treatment of colorectal cancers.