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

Liu, Zhinan; Shi, Yejiao; Zhang, Shuai; Wu, Shaojie; Wang, Zhe; Liu, Runhui; Hu, Honggang; Li, Xiang · Nano Lett · 2026

basic_science · Level V

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Abstract

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 mPEG<sub>1000</sub> groups surrounding a hydrophobic core made up of a therapeutic stapled peptide. <i>In vivo</i>, 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.