Lithium salts have remained the gold standard pharmacological treatment for bipolar disorder for over seventy years, yet the mechanistic basis of their therapeutic action is unknown. A central barrier to mechanistic investigation is the absence of chemical tools capable of delivering Li+ with spatial and temporal precision — current dosing is systemic, providing no means to isolate which biological pathways lithium modulates or when. We propose to address this gap through the design of selective host molecules that bind lithium and release it on demand using light as a stimulus.

The primary challenge is thermodynamic: Li+ binds water exceptionally tightly, and existing macrocyclic host molecules cannot overcome this barrier under biologically relevant conditions. To address this, we will synthesize a library of crown ether-based hosts and systematically map the structural features that govern aqueous Li+ binding. The most promising candidates will be equipped with a photocleavable unit, enabling light-triggered release. This work will provide both a generalizable framework for Li+ chelation and the first platform for controlled lithium delivery in biological systems.