Bioorthogonal Regulation of Self-Immolation and Controlled Release Using Cucurbit[7]uril Supramolecular Chemistry

Self-immolative chemistry has received significant attention in drug delivery and controlled release, leveraging a unique mechanism where a triggering event initiates a reaction cascade that releases molecular payloads. Herein, we introduce the concept of supramolecular gated self-immolative chemistry, allowing for the control of covalent bond scission through noncovalent host-guest interactions. Supramolecular regulation of self-immolation is exemplified using a newly designed ethylenediamine-based, bis-benzylated self-immolative entity (SIE) SIE2 in combination with the bioorthogonal cucurbituril-meditated host-guest system. The SIE2 engages in supramolecular complexation with cucurbit[7]uril (CB) host molecules, which effectively masks its reactivity and prevents premature initiation of the self-immolative cyclization–elimination cascade. The introduction of a com-petitive guest molecule 1-adamantylamine triggers the removal of the supramolecular CB capping group from the CB-SIE2 complex, revealing the nascent self-immolative structure. This decomplexation initiates a rapid cyclization-elimination cascade that releases the loaded cargo molecules from SIE2. As a proof-of-concept, we capped a self-immolative methylene blue pro-drug SIE5 with CB. The subsequent addition of 1-adamantylamine reactivated the self-immolation, initiating the controlled release of the therapeutic photosensitizer and on-demand activating photodynamic therapy for cell killing.