An Activatable Polymeric Nanoprobe for Fluorescence and Photoacoustic Imaging of Tumor‐Associated Neutrophils in Cancer Immunotherapy

Abstract Imaging to evaluate tumor‐associated neutrophils (TANs) is imperative for cancer immunotherapy but remains challenging. We herein report an activatable semiconducting polymer nanoprobe (SPCy) for near‐infrared fluorescence (NIRF) and photoacoustic (PA) imaging of neutrophil elastase (NE), a biomarker of TANs. SPCy comprises a semiconducting polymer conjugated with a hemicyanine (hemi‐Cy) dye caged by a NE‐cleavable peptide as the side chain. After systemic administration, SPCy passively targets the tumor and reacts with NE to “uncage” the hemi‐Cy, leading to enhanced NIRF and PA signals of the hemi‐Cy but unchanged signals of the SP. Such NE‐activated ratiometric NIRF and enhanced PA signals of SPCy correlate with the intratumoral population of TANs. Thus, this study not only presents the first TAN‐specific PA probe, but also provides a general molecular design strategy for PA imaging of other immune‐related biomarkers to facilitate screening of cancer immunotherapeutics.