Engineering liposomes via click chemistry for multimodal biomedical applications: Evidence from eukaryotic transfection and antimicrobial light-triggered therapy

Click chemistry is a powerful and versatile method for grafting various moieties onto a chemical backbone, enabling the integration of multiple functionalities into a single molecular scaffold. Here, a previously reported cationic lipophosphoramidate, BSV36, was employed in a series of liposomes functionalized with either a naphthalimide or a nitroaniline moiety. These modifications were introduced via aminolysis of phosphonodithioester click reaction, performed either before or after liposome formation. The various liposomes obtained could display - separately or in combination - multiple properties, i.e., fluorescence, nitric oxide (NO) photorelease, and reactive oxygen species (ROS) photogeneration. They were used to conduct a series of assays providing proof-of-principle that a single click-modified liposomal preparation can fluorescently label and photo-inactivate clinical bacterial strains, particularly Staphylococcus aureus, as well as to deliver plasmid DNA into human-derived cell lines. Importantly, comparison of liposome performance enabled the evaluation of the compatibility of the aforementioned features within a single entity. This work therefore offers new insights into the broadened applications of multimodular nanovesicles across diverse biomedical fields. In particular, it highlights their relevance for the treatment of recalcitrant infections in the context of genetic diseases, where the combined implementation of gene therapy and antimicrobial control could provide substantial therapeutic benefit.