Programmable molecular dethreading towards tunable drug release.

Precise control of molecular motion is essential for artificial molecular machines. Pseudorotaxane dethreading, a key process within interlocked architectures, offers a means to regulate such motion. However, achieving predictable and programmable control over dethreading kinetics remains challenging. Here, we achieve systematic modulation of dethreading behaviour through component engineering, using a pseudorotaxane platform composed of 24-crown-8-based macrocycles and adjustable benzylic amine stoppers. Activation energies are continuously tunable across the range of 22 to 30 kcal/mol, with a resolution as fine as 0.5-1.5 kcal/mol. Crystallographic analyses and computational modeling elucidate the dethreading pathway and the structure-kinetic relationships. As a proof-of-concept, representative assemblies are functionalized with the anticancer agent camptothecin. The resulting pseudorotaxanes display a consistent trend between their dethreading rates and cytotoxic potency. This work bridges molecular-scale mechanical motion with biological effects and provides a generalizable strategy for the design of programmable drug delivery systems. The pseudorotaxane toolkit reported here lays the foundation for the development of advanced molecular machines in biomedical applications.