This work introduces a new strategy to regulate self-immolative chemistry and molecular release using bioorthogonal cucurbit [7]uril-mediated host-guest interactions (Figure ). We rationally designed a subset of self-immolative guest molecules SIE1, SIE2, and SIE3 (Figure ) to form complexes with the bioorthogonal cucurbit [7]uril (CB) host molecules. The reactivity of CB-capped SIE2-referred to as CB/SIE2, where CB essentially serves as a 'supramolecular protecting group' masking the reactive functional groups in SIE2-was suppressed up to over 200 times under our experimental conditions, effectively preventing premature payload release through the cyclizationelimination cascade. The introduction of a competitive guest molecule, the FDA-approved 1-adamantylamine, triggers the disassembly of CB/SIE2 complex. The removal of the supramolecular CB protecting group reveals the nascent self-immolative structure, initiating a rapid cyclization-elimination cascade that releases the loaded cargo molecules. As a proofof-concept, we developed a self-immolative methylene blue prodrug SIE5, whose reactivity is suppressed when caged in the form of a CB/SIE5 supramolecular complex. The addition of 1adamantylamine decomplexes the CB/SIE5 and triggers the self-immolation of SIE5, leading to the release of the photosensitizer payload and activating photodynamic therapy on demand. This mechanistically novel strategy of regulating covalent bond scission through noncovalent and bioorthogonal host-guest interactions holds promise for various applications in targeted drug delivery, controlled release, self-immolative materials, and beyond.