Iontronic Click-to-Release Enables Electrically Controlled Delivery of Drugs and Biomolecules Beyond Charge and Size Limitations

Abstract

Dynamic and programmable control of therapeutic delivery is a long-standing goal in medicine. Iontronic devices offer precise electronic control over the dosage of bioactive molecules, yet their use has been confined to charged, low-molecular-weight compounds that are electrochemically stable during transport. Here, we present a hybrid delivery platform that integrates iontronic transport with bioorthogonal click-to-release chemistry. In this system, iontronic pumps electrophoretically deliver charged tetrazines as molecular scissors that selectively react with immobilized trans-cyclooctene (TCO)-linked payloads, enabling on-demand bioorthogonal cleavage of the TCO linker and controlled release. This approach retains the electronic precision of iontronics while overcoming molecular size, charge, and stability constraints. We demonstrate tunable tetrazine delivery over several days and electronically controlled release of immobilized payloads from small bioactive molecules, such as the antimitotic agent CA-4, to the large protein bovine serum albumin. Hence, by integrating bioorthogonal click-to-release strategies, iontronic delivery is extended to biologically relevant macromolecules, providing a foundation for next-level programmable electroceutical devices.