The concept of self-immolative linkers was first introduced by Katzenellenbogen and colleagues and has gained significant attention in diverse fields such as medicinal chemistry, polymer chemistry, and materials science. Self-immolative entities (SIEs) have evolved from traditional protecting group strategies where reactive functionalities were temporarily masked to modify reactivity, subsequently unmasked through selective cleavage under desired triggering environment. Although the terminology varies, a typical SIE comprises a trigger, a linker, and a cargo moiety. Triggering the protecting group causes bond fragmentation in the SIE through mechanisms such as electronic cascade or cyclization elimination ultimately releasing the cargo molecules. While physical stimuli such as temperature, light, mechanical force, and ultrasound are useful in spatiotemporally regulating self-immolative chemistry in different applications, their use in biological settings can be constrained by limited tissue penetration capabilities and needs for specialized equipment. On the other hand, chemical stimuli such as redox, pH changes, and enzymes have been used to achieve smart systems for targeted delivery and controlled release. However, off-target expression of these chemical signals in healthy tissues compromises the selectivity of chemical stimuli-responsive strategies, potentially leading to undesired drug leakage and adverse side effects. To address these challenges, the utilization of bioorthogonal chemistry to regulate self-immolation presents a promising venue for precise control of cargo release. Bioorthogonal chemistry refers to highly specific chemical reactions that can occur inside living systems without interfering with native biochemical processes and has been coupled with controlled release systems. Non-covalent chemistry is emerging as an alternative approach to covalency for forming unnatural complexes in living systems for applications such as cell labeling. Besides its potential for reversibility, non-covalent chemistry benefits from not being dependent on secondorder rate constants or highly activated reagents, which are major challenges present in developing bioorthogonal reactions. Instead, the emphasis is on achieving high binding affinities (Ka). A group of synthetic pumpkin-shaped macrocyclic molecules known as cucurbit[n]urils (n = 5-8, 10, 13-15) have attracted increasing attention in medicinal chemistry and biomedical applications due to their high affinity and highly selective binding interactions which typically do not interfere with biological systems. These characteristics have rendered cucurbit-mediated host-guest chemistry promising for a range of biological applications, such as proteins and biomolecule labeling, cellular and animal imaging, modulating dynamic DNA chemistry, and protein aggregation, controlling bioorthogonal catalysis, and protein separation. Of particular interests are cucurbit[n]uril-mediated supramolecular drug delivery systems encapsulating physically entrapped therapeutic agents. A popular strategy involves encapsulating engineered small molecule drugs in the cucurbit[n]uril cavity through non-covalent host-guest interactions to downregulate their bioactivity, while introducing a competitive guest molecule with a higher binding affinity enables the ondemand release of the 'caged' therapeutic molecule and activation of its therapeutic effects. 66-70 Moreover, cucurbit[n]urilbased chemistry has been innovatively used to construct selfassembling DNA-small molecule chimeras, nanomaterials, and hydrogel networks for the delivery of therapeutics. Beyond conventional chemotherapy, cucurbit[n]uril-mediated supramolecular chemistry has also been innovatively applied to regulate advanced therapeutic modalities such as photodynamic therapy and photothermal therapy, gene therapy, and supramolecular nanoassemblies. However, the scope of therapeutic guests whose therapeutic effect can be controlled by host-guest interactions remain limited. Their structures usually need to be engineered to simultaneously achieve high binding affinity and maintain bioactivity. A general approach that enables the supramolecular regulation of diverse therapeutic structures and allows for the release of drugs in their native forms remains an undeveloped yet transformative research avenue.