Cationic nanotrap curbs UVB-induced cutaneous photodamage via exosomal cfNA capture

Cell-free nucleic acids (cfNAs) carried by exosomes released from UVB-damaged skin cells act as damage-associated molecular patterns (DAMPs) that amplify sterile inflammation and contribute to sunburn, photoaging, and skin tumorigenesis. We isolated exosomes and cfNAs from UVB-irradiated human dermal fibroblasts (HDFs) and epidermal keratinocytes (NHEKs) and demonstrated that exosomes mediate the release and propagation of cfDNA, cfRNA, and cfmiRNA. These cfNAs activate endosomal Toll-like receptors (TLR3 and TLR9) and downstream NF-κB signaling in both reporter and recipient cell assays. To scavenge these inflammatory ligands, we engineered a 2D cationic nanosheet (WSP) by stabilizing exfoliated tungsten disulfide (WS₂) with salvianolic acid B (SAB) and grafting cationic PAMAM generation-1 dendrimers. WSP inhibited TLR3 and 9 activation induced by nucleic-acid agonists, UVB-conditioned media from HDFs and NHEKs, and exosomes derived from UVB-damaged HDFs, indicating effective neutralization of both soluble and vesicle-associated cfNAs. Mechanistically, WSP acts upstream of receptor engagement by electrostatically sequestering anionic cfNAs rather than directly blocking TLRs. Compared with SP1 (SAB-P1 lacking the WS₂ backbone), WSP more potently suppressed cfNA-associated inflammation and UVB-induced skin injury, with improved therapeutic efficacy in a murine UVB-induced skin inflammation model. Overall, WSP functions as an advanced "nanotrap" that enhances cfNA scavenging, attenuates inflammation, and helps reverse the progression of UVB-mediated skin damage.