DNA Molecular Robot for Osteosarcoma Therapy and Bone Regeneration

Abstract Preventing tumor recurrence while promoting bone regeneration remains a major challenge for osteosarcoma implants after limb-salvage surgery. Herein, we developed a DNA molecular robot (DMR) that converts tumor microenvironment (TME) and near-infrared (NIR) stimuli into integrin-mediated mechanical forces, generating microtubule-targeting activity without drugs. The DNA–polypeptide chimera contains RGD peptides for integrin anchoring and allosteric DNA switches with tunable piconewton sensitivity. Under acidic TME and NIR irradiation, DMR modulates microtubule dynamics, suppresses adhesion protein expression through the FAK–Src pathway, and disrupts mitotic spindle formation. Consequently, DMR selectively eliminates osteosarcoma cells, reducing tumor volume by 81.5%, while simultaneously enhancing bone regeneration with a 2.1-fold increase in trabecular thickness. By transducing integrin-mediated forces into intracellular microtubule regulation, DMR provides a nonpharmacological strategy for dual-functional implants with synergistic antitumor and osteogenic activities.