A tetrahedral framework DNA-based bioswitchable miR-26a-5p delivery system for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease with severely limited therapeutic options. MicroRNAs, especially miR-26a-5p, have exhibited potent anti-fibrotic effects in preclinical studies. However, their clinical translation has been impeded by intrinsic susceptibility to enzymatic degradation in physiological environments and poor cellular internalization efficiency. In this study, we developed a tetrahedral framework nucleic acid-based bioswitchable miRNA delivery system, termed BiRDS26, for the targeted delivery of miR-26a-5p. BiRDS26 demonstrated robust anti-fibrotic activity in both in vitro and in vivo models, mechanistically mediated by the coordinated suppression of the Hippo and Wnt signaling pathways. Collectively, these results position BiRDS26 as a rationally engineered nanotherapeutic platform with significant translational potential for IPF treatment.