Myelin-Inspired 3D PEGylation of Framework Nucleic Acids Enables Simultaneous Long Circulation and Rapid Renal Clearance

Abstract The rational design of nanomedicines is fundamentally constrained by a physicochemical paradox at the bio-nano interface: strategies to prolong circulation inevitably suppress clearance, often resulting in long-term accumulation and systemic toxicity. To address this, we propose spatial conformation engineering as an additional design dimension to decouple these opposing processes. Inspired by the compact, multilamellar architecture of the myelin sheath, we program poly(ethylene glycol) (PEG) chains into a three-dimensional matrix on a DNA tetrahedral framework. Unlike conventional linear or planar PEGylation, this 3D conformation yields a dense yet compact interfacial topology, enabling effective dynamic steric shielding (reducing protein adsorption by >60%) while maintaining a small hydrodynamic diameter (7.2 nm). This design strategy achieves a two-fold extension of blood circulation half-life while promoting a dominant renal elimination pathway (>90% clearance within 24 h). As a proof-of-concept, we functionalize the platform with a bile acid aptamer to construct a “patrolling” detoxification system capable of continuous sequestration and removal of blood-borne toxins in a murine hypercholanemia model. Our work establishes spatial conformation as a programmable parameter for regulating nanoparticle biodistribution and clearance, thereby shifting the design paradigm from compositional adjustment to architectural control. This architectural control opens avenues for targeted delivery, imaging, and immunotherapy.