Dendrimers with a far-red NDI fluorescent core for efficient and traceable gene and RNA delivery

Dendrimer-based nucleic acid (NA) delivery systems have attracted significant attention due to their synthetic versatility, monodispersity, nuclease resistance, high payload release, and transfection efficiency. The conventional dendrimers are non-fluorescent, limiting their utility in real-time tracking and monitoring of drug delivery. Although terminal functionalization with fluorophores can partially address this issue, it often alters critical physicochemical properties and transfection efficiency. In this study, we report the design and development of far-red fluorescent dendrimers with a naphthalene diimide (NDI)-core for efficient and traceable gene and RNA delivery. These intrinsically fluorescent dendrimers enable real-time monitoring of cellular uptake and delivery. The NDI G3 formulation effectively condenses DNA, protects it from DNase-mediated degradation, and facilitates efficient transfection in cells. Therapeutically, NDI G3 demonstrated efficient glutathione peroxidase 4 (GPX4) siRNA delivery, comparable to PAMAM G3 and Lipofectamine 3000. Notably, the NDI G3-Ca²⁺-GPX4 siRNA-FINO2 formulation sensitizes human colon cancer-derived cells to ferroptosis, synergistically annihilating cancer cells compared to treatment with FINO2 alone. The intrinsically far-red fluorescent NDI G3 dendrimer with a dynamic fluorescence response developed for the combinatorial delivery of siRNA and drug molecules offers a generalized framework for designing next-generation far-red fluorescent dendrimers for nucleic acid therapeutics and theranostic applications.