Mechanical Programming of Hollow DNA Nanocapsules Rewires In Vivo Trafficking

DNA nanostructures are programmable, biocompatible platforms for biomedicine; however, their mechanical properties are coupled to sequence and structural dimensions, limiting control over stiffness. Here, we report a paradigm shift from static design to mechanical engineering of DNA nanostructures. Using a nanoemulsion interfacial‐confined coordination assembly strategy, hollow DNA nanocapsules (HDCs) were constructed with mechanical properties decoupled from chemical identity, without hard templates. By tuning the nanoemulsion‐to‐DNA‐solution ratio, HDCs with sizes (∼160 nm) and surface charges (∼‐20 mV), yet adjustable shell thicknesses (8–72 nm) and Young's moduli (8–180 MPa), were achieved while preserving DNA function and enabling DNA to serve as scaffold and therapeutic cargo. Proteomic profiling revealed stiffness‐dependent remodeling of protein corona: soft HDCs enriched dysopsonins, whereas hard HDCs recruited complement and coagulation factors, producing a “corona switch” modulating pharmacokinetics and biodistribution. Consequently, soft HDCs exhibited prolonged circulation ( t 1/2 = 8.8 h vs 4.5 h), enhanced tumor accumulation (1.9‐fold higher at 8 h), reduced hepatic sequestration, and increased kidney distribution versus hard HDCs. As a proof of concept, antisense‐based 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.