Recognition-induced destabilization: controlled release from molecularly imprinted chitosan nanoparticles <i>via</i> specific, non-catalytic enzyme recognition

This work introduces a novel paradigm for stimuli-responsive drug delivery: recognition-induced destabilization, where specific molecular recognition-without enzymatic catalysis-triggers nanoparticle disassembly. We engineered chitosan-phthalate nanoparticles (NPs) <i>via</i> molecular imprinting using lysozyme or α-glucosidase as templates. Critically, these enzymes do not catalytically degrade deacetylated, cross-linked, chitosan NPs enabling isolation of the recognition effect. Upon recognition by their respective enzyme, the imprinted nanoparticles (nanoMIPs) exhibited selective structural destabilization confirmed by Dynamic Light Scattering (DLS), while non-imprinted controls remained stable. This recognition event facilitated highly specific, on-demand release of encapsulated ciprofloxacin, achieving >90% release compared to <11% from controls. These findings demonstrate that imprint-guided recognition, coupled with proximity-induced microstructural degradation, can induce catastrophic mechanical failure of nanoMIPs and trigger drug release. The high specificity, stability, and responsiveness of this platform highlight its potential for translation into targeted therapies, biosensing, and diagnostic applications. Future studies will explore <i>in vivo</i> performance in enzyme-rich microenvironments such as infection and inflammation sites.