Shell‐Crosslinked Hyaluronic Acid Nanogels for Live Monitoring of Hyaluronidase Activity In Vivo

A hyaluronidase (HAdase) has been noticed as a potential drug target as well as prognostic marker because of its close associations with tumor invasion, metastasis, and angiogenesis. Accordingly, precise monitoring of HAdase activity in vivo seems to be crucial not only for the evaluation of HAdase activity but also for non‐invasive molecular imaging. In our study, we propose a new organic, near‐infrared fluorescence imaging probe, indocyanine green (ICG)‐based stimuli‐responsive fluorescence probe for selective imaging of HAdases with appreciable signal‐to‐noise (S/N) ratios in serum and in vivo. Shell‐crosslinked hyaluronic acid (HA) nanogels (sc‐nanogels) are generated via a reducible covalent linkage which incorporate ICG derivatives. The ICG‐embeded HA nanogels via shell‐crosslinking have preferable properties for ideal selective imaging and detection of HAdase activity in vivo. The sc‐nanogels exhibit prominent chemical stability against external light, greatly control background signals in serum, and small size compared to use of self‐assembled ICG‐based carriers. Collapsed ICG in the hydrogel core is selectively disentangled by HAdase treatment for selective near‐infrared imaging without unwanted background signal. The newly designed sc‐nanogels may have great potential to serve as probes for improved selective imaging of HAdase‐associated diseases in clinics as well as HAdase‐activity screening in vivo.