A “Snooker”‐Inspired Nanoplatform Based on Apoptotic Body Relay Dismantles Neutrophil‐Macrophage Crosstalk for Rheumatoid Arthritis Therapy

ABSTRACT

Rheumatoid arthritis (RA) progression is driven by the vicious inflammatory crosstalk between neutrophils and macrophages, wherein the formation of neutrophil extracellular traps (NETs), abnormal glycolysis, and the STING pathway activation occur in macrophages. However, current nanomedicines are difficult to sequentially dismantle neutrophil‐macrophage crosstalk. Herein, inspired by the “snooker sequential shot” game, we develop a biomimetic nanoplatform (SOR@NNM) using endogenous neutrophil apoptotic bodies (ABs) as a relay to achieve the sequential regulation of neutrophils and macrophages. SOR@NNM is constructed by self‐assembling Roburic acid (RBA, a glycolysis inhibitor), SN001(a STING inhibitor), and a ROS‐responsive molecule (4‐OXi) to form a ternary complex nano‐core (SOR), coating with a neutrophil membrane modified by elastase‐binding peptide (NEBP). In the first stage, SOR@NNM targets activated neutrophils at the inflammatory site and inhibits NETs formation, thereby inhibiting anti‐citrullinated protein antibodies (ACPAs) generation at the source. In the second stage, endogenous ABs encapsulating RBA and SN001 are taken up by macrophages, synergistically blocking glycolysis and the STING pathway, thereby dismantling neutrophil‐macrophage crosstalk and remodeling the joint immune microenvironment. Animal experiments demonstrate that SOR@NNM significantly alleviates joint inflammation and structural damage, and improves locomotor function in rats. Our strategy offers a novel approach for RA treatment.