Systemic administration of antibiotics can cause severe side-effects such as liver and kidney toxicity, destruction of healthy gut bacteria, as well as multidrug resistance. Here, we present a bio-orthogonal chemistry-based strategy toward local prodrug concentration and activation. The strategy is based on the inverse electron-demand Diels–Alder chemistry between trans-cyclooctene and tetrazine and involves a biomaterial that can concentrate and activate multiple doses of systemic antibiotic therapy prodrugs at a local site. We demonstrate that a biomaterial, consisting of alginate hydrogel modified with tetrazine, is efficient at activating multiple doses of prodrugs of vancomycin and daptomycin in vitro as well as in vivo. These results support a drug delivery process that is independent of endogenous environmental markers. This approach is expected to improve therapeutic efficacy with decreased side-effects of antibiotics against bacterial infections. The platform has a wide scope of possible applications such as wound healing, and cancer and immunotherapy.

This communication describes a general approach for site-specific fluorescence labelling of RNA using a cytidine triphosphate (CTP) analogue derivatized with a trans-cyclooctene group. The analogue was efficiently incorporated into a model RNA strand using in vitro transcription. Bio-orthogonal reaction with fluorescein-labelled tetrazine was utilized to fluorescently tag the synthetic RNA strand.

A general strategy for purification of oligonucleotides synthesized by solid phase synthesis is described. It is based on a recently developed concept involving a bio-orthogonal inverse electron demand Diels-Alder reaction between trans-cyclooctene and tetrazine, termed 'click-to-release'. The strategy has been applied towards the synthesis and purification of a model hairpin RNA strand, as well as a 34 nt long aptamer.