Abstract
Lupus nephritis (LN) poses a severe risk for individuals with systemic lupus erythematosus (SLE), prompting extensive research into targeted delivery systems capable of modulating immune responses and clearing cell-free DNA (cfDNA). Here, we propose a novel renal homing nanogel that acts as a cfDNA scavenger and a dexamethasone (DXM) delivery carrier for LN treatment. Based on the generation 3 polylysine dendrimers, the created cationic nanogels (G3DSP) exhibit minimal toxicity and outstanding DXM loading efficiency. Our studies confirm that these nanogels can competitively bind with anionic cfDNA in vitro, leading to the suppression of toll-like receptor 9 (TLR9) activation. When administered systemically to MRL/lpr mice, the nanogels preferentially localize to and are retained in the inflamed kidneys, releasing their payload in response to reactive oxygen species (ROS), therefore effectively ameliorating SLE symptoms. Consequently, G3DSP nanogels emerge as a promising effective combined therapy for LN, minimizing cfDNA accumulation in vital organs and delivering immunomodulatory benefits through DXM.