Mussel Foot Protein Membrane‐Enclosed Crystalline Drug with Zero‐Order Release Kinetics for Long‐Acting Therapy

Abstract Injectable formulations with sustained and steady release capabilities are critically required to treat diseases requiring temporary or lifelong continuous therapy, especially for drugs with a short half‐life. Additionally, achieving a sufficiently high drug loading in a single dose remains a persistent challenge. Herein, by mimicking the formation principles of mussel adhesive plaques, we have developed membrane‐enclosed crystalline systems of insulin and progesterone as model macro‐ and small‐molecular crystalline drugs. The system exhibits a substantial drug loading capacity (>90 %). It exhibits sustained and zero‐order release kinetics, thereby facilitating the establishment of a subcutaneous reservoir containing a substantial drug load, enabling progressive and continuous release of the drug into the body. One single injection of membrane‐enclosed insulin crystal can maintain normoglycemia in diabetic mice for up to 7 days. Meanwhile, membrane‐coated progesterone crystals can sustain drug release in rats for over 7 days. The protein membrane can be cleared from the injection sites in 35 days. This system can serve as a versatile platform for the sustained release of various crystalline pharmaceuticals and the treatment of distinct diseases.