Targeted DNA Nanomachine Enables Specific miRNA‐Responsive Singlet Oxygen Amplification for Precise Cutaneous Squamous Cancer Therapy

Abstract Photodynamic therapy (PDT) is a promising strategy for the treatment of skin‐related tumors including cutaneous squamous cells carcinoma (cSCC). However, it is hard to balance the dosage off‐target phototoxicity while maintaining satisfactory therapeutic effect. In addition, oxygen‐dependent photosensitizers (PSs) are affected by tumor hypoxic environment, which further causes inefficient photocatalysis and reduces therapeutic effect. Herein, an intelligent DNA nanomachine based on tetrahedral DNA framework is proposed, incorporated with tumor‐targeted aptamer and specific miRNA‐responsive hairpin DNA catalytic assembly (HCA), for precise and high‐efficient therapy of cSCC. After aptamer‐mediated targeted delivery, a cSCC‐specific miRNA selected by tissue sequencing analysis is used to activateHCA, for amplifying PSs and controllably releasing chemotherapeutic drugs. Sequential recognition can greatly improve tumor‐specific accumulation and high‐dose activation. Moreover, hemin is incorporated into DNA to catalytically produce oxygen. In vitro and in vivo experiments demonstrated that this DNA nanomachine greatly improved anti‐tumor effect and realized effective ablation of cSCC in mice, with barely systemic toxicity and inflammation. It is anticipated that this strategy will promote biomedical applications of tumor‐specific miRNA and provide a promising option for the non‐invasive treatment of skin‐associated tumors.