Fig. 6: Overview of the proposed mechanism of siIRF5@EINI-induced inflammatory regulation in RA.

a To manipulate the locoregional exposure of the phosphatidylserine (PtdSer) corona of the designed nanoimitator intra-articularly, a benzeneboronic acid pinacol ester group was used to make the nanoimitator responsive to local ROS stimuli. The ROS-abundant inflamed joint microenvironment triggers PtdSer presentation of the nanoimitator. In an efferocytosis-like manner, the PtdSer-coroneted core is in turn phagocytosed by synovial inflammatory macrophages, which synergistically terminate the SIM-initiated pathological cascades that pro-inflammatory cytokine production, oxidative stress, and recruitment of neutrophils. b Schematic illustration showing that the efferocytosis-informed nanoimitator terminates SIM-initiated pathological cascades, synergistically restores articular immune homeostasis, and ultimately reverses bone erosion. The siIRF5-carrying efferocytosis-informed nanoimitator (siIRF5@EINI) consisted of a drug-based core with an oxidative stress-responsive PtdSer corona and a shell composed of a P-selectin-blocking motif, low molecular weight heparin (LMWH). With the shielding of LMWH, siIRF5@EINI is endowed with stealth properties in the circulation, enhanced retention in inflamed regions, and a blocking function of P-selectin that retards the articular trafficking of neutrophils. Upregulated ROS triggered shell exfoliation and the PtdSer corona is then exposed. In an efferocytosis-like manner, the PtdSer-coroneted core is in turn phagocytosed by SIMs, which synergistically terminate SIM-initiated pathological cascades and serially reestablish intra-articular immune homeostasis, conferring a chondroprotective effect.