The design of enzyme mimics from stable and nonprotein systems is especially attractive for applications in highly specific cancer diagnosis and treatment, and it has become an emerging field in recent years. Herein, metal crosslinked polymeric nanogels (MPGs) were prepared using Fe ion coordinated biocompatible acryloyl-lysine polymer brushes obtained from an enzyme-catalyzed atomic transfer radical polymerization (ATRPase) method. The monoatomic and highly dispersed Fe ions in the MPGs serve as efficient crosslinkers of the gel network, and also as active centers of multienzyme mimics of superoxide dismutase (SOD) and peroxidase (POD). The catalytic activities were compared to those of conventional Fe-based nanozymes. Studies on both cells and animals verify that efficient reactive oxygen species (ROS) responsive biofluorescence imaging can be successfully realized using the MPGs.