Neutrophil extracellular traps-inhibited nanoplatform achieves comprehensive treatment of rheumatoid arthritis at different stages.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by cartilage and bone erosion. The development process of RA could be divided into early, full blown, and late stages. The pathogenesis of those stages is still far from fully understood, which poses a tremendous challenge for developing nano-preparations for efficiently treating RA across all phases. Activated neutrophils continuously infiltrate inflamed joints and exacerbate joint cartilage and bone damage by releasing neutrophil extracellular traps (NETs). Therefore, constructing a drug delivery system based on inhibiting NETs is beneficial for blocking a series of inflammatory response cascades and joint injuries, achieving effective treatment of RA at various stages. To achieve targeted treatment of inflamed joints, we utilized the phagocytic function and migratory chemotaxis of activated neutrophils to design a drug delivery system (BTST NPs) that could hitchhike activated neutrophils to arrive at the inflamed joints. BTST was synthesized by conjugating bovine serum albumin (BSA) and sivelestat (ST) via ROS-sensitive thioketal bonds. Activated neutrophils could engulf BTST NPs through specific binding between Fcγ receptors and BSA, and transport BTST NPs to inflamed joints. In vitro studies showed that BTST NPs could release ST in response to ROS to block NETs release. In vivo biodistribution and pharmacological experiments illustrated that BTST NPs could be efficiently transported by activated neutrophils to inflamed joints and exhibit favorable therapeutic effects across different RA stages. The construction of BTST NPs provides a new strategy for functional integration in treating RA at various stages.