From Covalent to Supramolecular: Re‐Thinking Lysosome‐Targeting Chimeras Through Modular and Tunable Proximity Control

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.