Work

Programmable molecular dethreading towards tunable drug release

Year: 2025

Type: article

Abstract: 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. Pseudorotaxane dethreading offers a means to regulate motion in artificial molecular machines but achieving predictable and programmable control over dethreading kinetics remains challenging. Here, the authors report systematic modulation of dethreading behaviour through component engineering of a pseudorotaxane platform.

Source: Nature Communications

DOI: 10.1038/s41467-025-64452-5