The nuclear envelope serves as a highly regulated gateway for macromolecule exchange between the nucleus and cytoplasm in eukaryotes. Here we have developed a cell nucleus-mimicking polymeric membrane-enclosed system for long and self-regulated therapy. A polymeric nano-membrane with nanopores is conformally synthesized in situ on the surface of each insulin crystal, ensuring sustained, adjustable and zero-order drug release kinetics. Glucose- and β-hydroxybutyrate-dually sensitive microdomains are integrated into the nano-membranes. Under a normal state, the microdomains are uncharged and the channel is narrow enough to block insulin outflow. Under hyperglycaemia and ketonaemia, microdomains convert the high glucose and β-hydroxybutyrate concentration signals to the negative electric potential of membranes, widening the nanopores with rapid insulin outflow. In type 1 diabetic mice and minipigs, this system can maintain normoglycaemia for longer than 1 month and 3 weeks, respectively, with validated glucose- and β-hydroxybutyrate-triggered insulin release. Such membrane-enclosed drug crystal/powder formulation provides a broad platform for long-acting controlled release.