Helix-Guarded Molecular Clips for Cell-Free DNA Scavenging and Treatment of Systemic Lupus Erythematosus

Immune disorders induced by cell-free DNA (cfDNA) account for the incidence and deterioration of systemic lupus erythematosus (SLE). Scavenging of cfDNA using cationic polymers represents a promising modality for SLE management. However, they bind cfDNA mainly via electrostatic interaction, which would result in an undesired discharge of the captured cfDNA upon competitive replacement by the negatively charged serum/intracellular components. Inspired by the natural recognition mechanism of biomacromolecules via spatial matching, we herein developed a library of dendrimer-templated, spherical, α-helical, and guanidine-rich polypeptides as molecular clips for cfDNA scavenging. Upon optimization of the polypeptide length and density on the dendrimer surface, the top-performing G3-8 was identified, which could tightly confine cfDNA within the cavity between the adjacent, rod-like α-helices. As thus, the helical G3-8 but not the random-coiled analogue _D,L-G3-8 enabled robust cfDNA scavenging under serum-rich conditions to inhibit TLR9 activation and inflammation. In SLE mice, i.v. injected G3-8 efficiently prevented organ failure and inhibited inflammation by scavenging cfDNA. This study provides an enlightened strategy to stably bind and scavenge cfDNA and may shift the current paradigm of SLE management.