Sclerostin-targeted silica-mineralized DNA origami enables reliable and synergistic osteoporosis therapy.

Abstract

Clinical antiresorptive drugs primarily target bone metabolism but often neglect the simultaneous oxidative stress and inflammation inherent in osteoporosis. Here we developed a novel triple-function nanoagent consisting of aptamer-silica-DNA nanopatch for reliable, targeted and synergistic osteoporosis treatment. We controlled the mineralization of DNA origami with silica via electrostatic interactions between silica precursors and DNA strands, achieving optimal mineralization at 23 %. This modification enhanced nuclease resistance-reducing degradation by 60.36 %-while preserving bone-targeting and reactive oxygen species-scavenging functions. Furthermore, functionalizing the nanopatch with FDA-approved sclerostin aptamers enabled specific binding to sclerostin, effectively reactivating Wnt signaling in osteoblasts to promote bone formation. In vivo studies demonstrated that the nanopatch reversed osteoporotic bone loss in ovariectomized mice, increasing bone density by approximately 30 % compared to bisphosphonate treatments. Overall, this triple-function nanopatch addresses structural instability, oxidative stress, and disrupted bone metabolism, offering a comprehensive therapeutic strategy for osteoporosis.