Subcutaneously injected Chinese herbal hydrogel as a NETs-scavenging niche for restoring immune homeostasis in lupus

Abstract Systemic lupus erythematosus (SLE) is a chronic inflammatory disease. It is characterized by multisystem involvement and potential damage to multiple organs, especially the kidneys, resulting in a substantial clinical burden. Current treatment strategies, including corticosteroids, biologics, and immunosuppressives, are often limited by their limited efficacy and side effects. Increasing evidence suggests that dysregulated neutrophil extracellular traps (NETs) and systemic inflammatory responses are closely related to the pathogenesis and progression of SLE. This suggests a potential immunomodulatory target. Inspired by the human immune niche, we developed a novel Chinese herbal hydrogel for lupus immunotherapy. By combining Rhein and deoxyribonuclease I (DNase I) with photo-crosslinkable hyaluronic acid, an injectable traditional Chinese medicine hydrogel was obtained. After subcutaneous injection, it can sustainably release active herbal ingredients, regulate systemic inflammation and effectively clear NETs. In vivo studies have shown that biomimetic hydrogels can not only improve systemic symptoms but also control renal lesions through sustained systemic intervention therapy. Hydrogel treatment can significantly alleviate the pathological changes related to lupus, reduce the level of inflammatory factors, and expand the number of regulatory T cells. It also improved immune cell infiltration and progression of lupus nephritis, emphasizing its ability to restore systemic immune homeostasis. Notably, transcriptome analysis revealed that hydrogels attenuate SLE by orchestrating down-regulation of neutrophil function and pathogenic processes of inflammation while enhancing antioxidant defense and immunomodulatory signaling. These findings suggest that the traditional Chinese herbal hydrogel system exhibits significant therapeutic potential as a biomimetic immune niche for SLE and may provide a promising platform for lupus treatment.