Pollen‐Inspired Aptamer Delivery System for Multi‐Target Therapy in Rheumatoid Arthritis

Abstract In rheumatoid arthritis (RA), the complex interplay of inflammatory mediators and cellular mechanisms presents challenges for effective treatment. Current therapies, often targeting singular pathways, achieve limited clinical remission. This study introduces a multifunctional therapeutic strategy using a pollen‐inspired aptamer delivery system (tk‐Apt@pollen) designed for dual targeting of neutrophil extracellular traps (NETs) and tumor necrosis factor‐alpha (TNFα). Engineered sunflower pollen grains, modified with methoxy polyethylene glycol (mPEG) and thioketal (TK), encapsulate aptamers that inhibit DEK protein activity and TNFα‐mediated inflammation. This dual mechanism disrupts NETs formation, mitigates reactive oxygen species (ROS) levels, and inhibits osteoclastogenesis. In vitro assays demonstrated the system's ability to inhibit NET production, reduce osteoclast activation, and achieve controlled aptamer release in response to ROS. In vivo, tk‐Apt@pollen significantly reduces joint inflammation and bone erosion in a collagen‐induced arthritis mouse model, outperforming free aptamers. This study highlights tk‐Apt@pollen as a promising approach to address the multifaceted pathology of RA, providing insights into designing multi‐target therapies for chronic inflammatory diseases.