Guanidine-Functionalized Aminoglycosides Enable miR-7a Delivery to Attenuate Neuroferroptosis

Abstract Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and increasingly recognized as a key contributor to neurodegeneration (neuroferroptosis). Current pharmacological approaches primarily target downstream ferroptotic events and do not address upstream epigenetic regulation. MicroRNA (miRNA)-mediated modulation represents a potential strategy to overcome this limitation, while its application is hindered by the lack of delivery vectors that combine efficient nucleic acid delivery with physiological compatibility. In this study, guanidinium-functionalized aminoglycosides (GAs) are investigated as a natural product-derived small-molecule carrier for miRNA delivery. GAs form stable nanocomplexes with miR-7a, an epigenetic regulator of neuroferroptosis, through multivalent guanidinium-mediated interactions, enabling efficient cellular uptake. Among the molecules evaluated, neomycin G (NEO G) exhibited enhanced miRNA binding, improved intracellular delivery, and functional activity under viscosity conditions closely recapitulating the extracellular milieu, wherein conventional delivery vectors typically display reduced efficacy. Delivery of miR-7a mimic using NEO G results in effective downregulation of Krüppel-like factor 4 (Klf4), a transcription factor implicated in neuroferroptosis, and confers significant neuroprotection via modulation of the miR-7a-Klf4 axis. These findings identify GAs as a biocompatible and effective platform for miRNA delivery and highlight their potential utility in miRNA therapeutic strategies targeting neuroferroptosis.