Highly Specific Targeting of Tumor Extracellular Matrix by a Sharply pH-Activated Single-Chain Collagen Mimetic Peptide Probe

Targeted detection of the tumor extracellular matrix (ECM) has emerged as a transformative strategy for early cancer diagnosis and precision therapy, offering broad applicability across diverse tumor types. Pathological collagen, a hallmark of tumor ECM remodeling, holds significant promise as a biomarker. However, existing peptide probes lack the specificity to distinguish tumor ECM from ECM alterations in noncancerous conditions. Herein, we design a sharply pH-activated single-chain collagen mimetic peptide probe, TEMPO, for highly specific tumor ECM-targeting. TEMPO integrates a triple-helix-stabilizing unit and a pH-responsive destabilizing unit to precisely regulate its conformation. Under physiological pH, TEMPO adopts an inactive triple-helix; while in the tumor microenvironment, TEMPO transforms to an active single-stranded conformation, triggered at pH 6.7 with a sharp response spanning less than 0.3 pH units at physiological temperature. The pH-activated TEMPO demonstrates exceptional specificity for pathological collagen within tumor ECM, distinguishing it from nontumor ECM across a broad spectrum of tumor types. TEMPO exhibits remarkable selectivity and efficacy in both NIR and MR imaging, underscoring its potential as a versatile tool for precise tumor detection. This tumor ECM-specific peptide probe represents a significant advancement in tumor diagnostics, offering a transformative approach to accurate imaging and diagnosis across diverse cancer types.