Work

Proteolysis activity mapping and substrate discovery platform for identifying tumor-activated biosensors

Year: 2026

Type: article

Abstract: Dysregulated extracellular proteolytic activity is a prominent hallmark of cancer and can thus be exploited for tumor detection and therapeutic development. However, the discovery of tumor-responsive probes has been hindered by the lack of methods to directly screen proteolytic events in specific tissue samples. Here we report PSurf, a platform that enables the identification of tissue-specific protease sensors with tissue specimens. Through differential selection of tumor-specific sequences over healthy tissue, PSurf identifies context-specific tumor-activated probes that precisely distinguish metastatic lesions in lung tissue slices. Using these substrates, we engineered nanobody-targeted biosensors that release urinary reporters upon tumor-specific cleavage in vivo, enabling precise non-invasive tumor detection in a mouse lung metastasis model. PSurf provides a foundation for developing conditionally activated agents through tissue-specific activity mapping and probe discovery.

Source: Nature Chemical Biology

DOI: 10.1038/s41589-026-02218-w