Cell-free DNA depletion via cell-penetrating poly(disulfide)s for rheumatoid arthritis therapy

Cell-free DNA (cfDNA)-induced inflammation is linked to various autoimmune diseases, though cfDNA scavenging for cationic polymers has been regarded as an efficient therapeutic pathway. However, most existing cfDNA scavengers have significant cytotoxicity and weakly binds to cfDNA. Here, an advanced cfDNA scavenging strategy via assembly of cfDNA is reported for rheumatoid arthritis (RA) therapy. In this study, we developed a pH-responsive calcium carbonate nanoplatform loaded with low-toxicity guanidinium-containing cell-penetrating poly(disulfide)s (CPDs, LA). The LA could strongly adhere to nucleic acid (NA) and further self-assemble into NA nanospheres. Importantly, the NA nanospheres could be directly delivered into the cell through thiol-mediated uptake, which avoided the activation of the endosomal toll-like receptors (TLRs), thereby inhibited CpG-activated inflammation. As a result, LA@CaCO3 effectively decreased the cfDNA level and alleviated the joint swelling and bone erosion on a collagen-induced arthritis (CIA) rat model of RA. Accordingly, the study proposes an advanced approach to deplete NA for autoimmune disease treatment.