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

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.