ABSTRACT Proximity‐based molecular strategies have reshaped chemical biology, yet their architectures remain dominated by covalent linkers that impose fixed stoichiometry and static control. Such rigidity limits adaptability, particularly in lysosome‐targeting systems that operate within highly dynamic trafficking environments. This concept reframes molecular linkage as a regulatable interface rather than a permanent connection, proposing supramolecular host‐guest interactions as a modular alternative to covalent bridges. By enabling reversible assembly and tunable stoichiometry, supramolecular proximity decouples target engagement from effector recruitment and introduces dynamic control over proximity outcomes. Extending beyond lysosome‐targeting degradation, this framework offers general design principles for proximity‐based modalities that rely on transient, spatially constrained, or context‐dependent interactions. Collectively, these insights position supramolecular interfaces as a conceptual expansion of chemically induced proximity, opening new avenues for adaptive and controllable molecular systems.
Wang et al. (Fri,) studied this question.