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 (t1/2 = 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.