Biomimetic hybrid nanoparticles for dual regulation of macrophage pyroptosis and metabolism in rheumatoid arthritis.

Rheumatoid arthritis (RA), a chronic and debilitating autoimmune inflammatory disease, is critically driven by macrophages within the inflamed synovium. The inflammatory cascade is sustained by a synergistic imbalance between macrophage pyroptosis and metabolic dysfunction, resulting in the formation of a dual barrier to effective intervention. GSDME-targeted siRNA delivery effectively blocks pyroptosis; however, uncorrected metabolic defects leave "saved" macrophages in a proinflammatory state, thereby aggravating RA. To address this "dual dilemma", folic acid-modified macrophage membrane-lipid hybrid nanoparticles (FA-MMLNPs) were engineered for spatiotemporally coordinated codelivery of GSDME siRNA (siG) and 4-octyl itaconate (4-OI). The biomimetic membrane promotes inflammatory homing, folic acid enhances FR-positive macrophage endocytosis, and the lipid core protects the siRNA and ensures synchronous release. Mechanistically, SiG inhibits pyroptosis, whereas 4-OI restores mitochondrial metabolism to reprogram macrophages to an anti-inflammatory phenotype. This integrated material platform organically combines pathway-specific gene silencing, metabolic correction, and precise biointerface engineering, providing a versatile paradigm for material design in RA and other inflammation-driven diseases.