Lactate-sensitive nanomachines for enzyme-controlled drug delivery in cancer therapy

Here, we report the preparation of a novel enzyme-powered nanomachine for a drug delivery system based on mesoporous silica nanoparticles capped with a cyclodextrin-lactate oxidase (CD-LOx) complex, which enables controlled cargo release triggered by the presence of L-lactate in the tumor microenvironment. To this end, mesoporous silica nanoparticles were functionalized with diphenylethane-1,2-dione moieties and subsequently loaded with a cargo molecule. In parallel, a CD-LOx complex was prepared to act as a capping agent through supramolecular interactions, enabling controlled release of the encapsulated molecules in response to L-lactate. These nanodevices were first evaluated using [Ru(bpy)₃]Cl₂, as a model cargo, to confirm the efficiency and specificity of the gating mechanism. Subsequently, the nanomachines were loaded with the anticancer drug doxorubicin and tested in cell culture experiments at a concentration of 50 µg L^-1. The results showed the best therapeutic response after 24 hours of incubation in the presence of 25 mM L-lactate, confirming that lactate-triggered H₂O₂ generation efficiently activates the molecular gates and promotes targeted drug release within the cellular environment. This work demonstrates the development of an autonomous lactate-responsive drug delivery system that enables selective and controlled drug release in tumor environments with high L-lactate levels.