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Due to their inherent characteristics, DNA nanostructures possess natural advantages as carriers for regulating gene expression in a non\u2010viral manner. Cholesterol modification can convert DNA nanostructures from hydrophilic materials to amphiphilic materials, thereby extending their systemic circulation time. In this study, the high\u2010dimensional design and cholesterol modification are shown to prolong the systemic circulation half\u2010life of DNA nanostructures in mice. Specifically, the tetrahedron structure modified with three cholesterol molecules (TDN\u20103Chol) exhibit excellent circulation time and demonstrate a preference for renal uptake. The unique characteristics of TDN\u20103Chol can effectively deliver p53 siRNA to the mouse renal tubular tissue, resulting in successful knockdown of p53 and demonstrating its potential for preventing acute kidney injury. Furthermore, TDN\u20103Chol is not exhibited significant toxicity in mice, highlighting its promising role as a non\u2010viral vector for targeted gene expression regulation in the kidneys. The designed non\u2010viral vector as a prophylactic medication shows potential in addressing the current clinical challenges associated with nephrotoxic drugs.<\/jats:p>","DOI":"10.1002\/smll.202311690","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T19:14:24Z","timestamp":1708456464000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cholesterol\u2010Modified DNA Nanostructures Serve as Effective Non\u2010Viral Carriers for Delivering siRNA to the Kidneys to Prevent Acute Kidney Injury"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7318-8284","authenticated-orcid":false,"given":"Chengxun","family":"Li","sequence":"first","affiliation":[{"name":"School of Stomatology &amp; Shanghai Stomatological Hospital Institutes of Biomedical Sciences Fudan University  Shanghai 200032 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