Requirements of Constrictive Binding and Dynamic Systems on Molecular Cages for Drug Delivery

Molecular cages have promising host–guest properties for drug delivery applications. Specifically, guest⊂cage complexes can be used for the on-command release of encapsulated guest molecules in response to specific stimuli. This research explores both the dynamic and constrictive binding guest⊂cage systems for drug encapsulation and release in biological environments. In dynamic systems, the guest rapidly passes in-and-out through the portals of the cage, enabling drug delivery in vitro but facing limitations in vivo due to dilution effects that result in guest release. These challenges are addressed by constrictive binding systems, where the guest is trapped in a “gate-closed” state within the cage. In these systems, the on-command release is triggered by a “gate opening” event, which lowers the guest–out energy barrier. A full guest release is achieved when the gate opening reduces the cage–guest affinity, making constrictive binding systems more effective for controlled drug delivery. As a result, this study shows that guest⊂cage complexes have suitable properties for drug delivery in biological contexts.