24:T54c,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.25:T537,Cell-free DNA (cfDNA), reactive oxygen species (ROS), and pro-inflammatory cytokines interplay to form a self-amplified inflammatory cascade in autoimmune diseases (AIDs), accounting for the limited efficacy of single-target therapeutic modalities. Herein, biomimetic nanoparticles (NPs), constructed from macrophage membrane (RM)-coated cerium oxide (CeO₂), are developed to concurrently scavenge multiple inflammatory mediators for AID management. Upon systemic administration, the NPs feature long blood circulation and targeted accumulation at the inflamed site. In the inflammatory microenvironment, RM with abundant cytokine receptors neutralizes varieties of pro-inflammatory cytokines, and CeO₂ with nuclease- and antioxidase-like activities scavenges multiple types of ROS. In addition, O₂ bubbles generated from CeO₂-catalyzed H₂O₂ decomposition foster membrane shedding and subsequent CeO₂ exposure for effective cfDNA cleavage. Thus, the NPs effectively interrupt the inflammatory cycle and promote tissue repair in mouse models of AIDs including rheumatoid arthritis and autoimmune hepatitis. This study provides an effective mechanism for the multi-target management of inflammation, which holds profound implications for the treatment of AIDs.

#	Concept	H-Index	Publications	Citations
1	Engineering	1	1	31
2	Medicine	1	1	31
3	Biomedical Engineering	1	1	31
4	Immunology	1	1	31
5	Cell Engineering	1	1	31

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