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Here, we report the design of DNA\u2010peptide\u2010PNA hybrid probes for sensitive imaging of protease activity within the acidic extracellular milieu of lesions, achieving enhanced spatial selectivity. In the strategy, both a pH\u2010sensitive peptide and a protease\u2010cleavable peptide substrate are rationally integrated into a DNA\u2010based signal amplification platform. Specifically, a pH (low) insertion peptide (pHLIP) enables controlled localization of a peptide\u2010substrate\u2010engineered DNA initiator on the cell membrane under acidic conditions. Subsequent protease\u2010mediated cleavage of the peptide substrate triggers signal amplification via initiator\u2010mediated hybridization chain reaction (HCR), resulting in markedly improved spatial controllability and detection sensitivity for extracellular protease profiling in diseased microenvironments. Furthermore, the molecular imaging capability of the DNA\u2010Peptide\u2010PNA hybrid system was validated for matrix metalloproteinase 2\/9 (MMP2\/9) in vivo using both 4T1 tumor and osteoarthritis models. These results highlight the potential of this strategy as a versatile platform for the specific imaging of diverse enzymes within extracellular environments characterized by pH dysregulation.<\/jats:p>","DOI":"10.1002\/anie.8169928","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T09:24:15Z","timestamp":1787390655000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatially Controlled Imaging of Proteases in Acidic Extracellular Milieu of Lesions Using DNA\u2010Peptide\u2010PNA Hybrid Probes"],"prefix":"10.1002","author":[{"given":"Xiulin","family":"Yi","sequence":"first","affiliation":[{"name":"CAS Key Laboratory For Biomedical Effects of Nanomaterials and Nanosafety National Center For Nanoscience and Technology  Beijing China"},{"name":"College of Materials Science and Optoelectronic Technology University of Chinese Academy of Sciences  Beijing 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