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Here, we report a paradigm shift from static design to mechanical engineering of DNA nanostructures. Using a nanoemulsion interfacial\u2010confined coordination assembly strategy, hollow DNA nanocapsules (HDCs) were constructed with mechanical properties decoupled from chemical identity, without hard templates. By tuning the nanoemulsion\u2010to\u2010DNA\u2010solution ratio, HDCs with sizes (\u223c160\u00a0nm) and surface charges (\u223c\u201020\u00a0mV), yet adjustable shell thicknesses (8\u201372\u00a0nm) and Young's moduli (8\u2013180\u00a0MPa), were achieved while preserving DNA function and enabling DNA to serve as scaffold and therapeutic cargo. Proteomic profiling revealed stiffness\u2010dependent remodeling of protein corona: soft HDCs enriched dysopsonins, whereas hard HDCs recruited complement and coagulation factors, producing a \u201ccorona switch\u201d modulating pharmacokinetics and biodistribution. Consequently, soft HDCs exhibited prolonged circulation (\n                    <jats:italic>t<\/jats:italic>\n                    <jats:sub>1\/2<\/jats:sub>\n                    = 8.8\u00a0h vs 4.5\u00a0h), enhanced tumor accumulation (1.9\u2010fold higher at 8\u00a0h), reduced hepatic sequestration, and increased kidney distribution versus hard HDCs. As a proof of concept, antisense\u2010based HDCs provided evidence that mechanical softening improved in vivo therapeutic performance. This work establishes mechanical modulus as a programmable parameter and provides a framework for regulating protein corona formation and systemic fate.\n                  <\/jats:p>","DOI":"10.1002\/anie.2946344","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:15:03Z","timestamp":1790075703000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanical Programming of Hollow DNA Nanocapsules Rewires In Vivo Trafficking"],"prefix":"10.1002","author":[{"given":"Fan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Chemistry Shanghai Stomatological Hospital &amp; School of Stomatology Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials State Key Laboratory of Molecular Engineering of Polymers Fudan University  Shanghai 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Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials State Key Laboratory of Molecular Engineering of Polymers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2752-7929","authenticated-orcid":false,"given":"Lifei","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Chemistry Shanghai Stomatological Hospital &amp; School of Stomatology Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials State Key Laboratory of Molecular Engineering of Polymers Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyue","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Shanghai Stomatological Hospital &amp; School of Stomatology Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials State Key Laboratory of Molecular Engineering of Polymers Fudan University  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