Exendin-4 has been clinically exploited for treating type 2 diabetes, but the short circulation half-life and multiple daily injections limit its widespread application with respect to poor patient compliance, low efficacy, and high treatment cost. In this study, a potent long-acting release system based on biomimetic mineralization was constructed for biocompatible and sustained exendin-4 delivery. Similar to natural biomineralization, exendin-4 can be mineralized to form nanosized mineral solids by means of the reaction between acidic amino acid residues and calcium ions in a supersaturated environment with negligible influence on peptide bioactivity. Mineralized exendin-4 particles may be spontaneously absorbed by a living body under physiologically supersaturated conditions, resulting in gradual dissociation and sustained drug release. In such a way, the glucose level of diabetic mice may be effectively controlled for a long period of time by mineralized exendin-4 without obvious side effects. We believe this biomimetic formulation can serve as a promising candidate for future clinical applications for type 2 diabetes therapies.