Leukocyte-mimicking nanoparticles for enhanced synovial targeting in autoimmune arthritis.

Conventional systemic therapy for rheumatoid arthritis (RA) is limited by poor synovial drug accumulation, rapid systemic clearance, and dose-dependent off-target toxicities. Although inflamed joints may permit partial passive nanocarrier accumulation, increased accumulation in the joints remains heterogeneous and often insufficient for reliable therapeutic delivery. Leukocyte-mimicking nanoparticles (LM-NPs) therefore represent a promising active targeting strategy for autoimmune arthritis by recapitulating key elements of leukocyte trafficking, including selectin-mediated rolling, integrin-dependent adhesion, chemokine-guided migration, and immune-evasive self-signaling, thereby constructing an unparalleled biomimetic targeting system. By incorporating leukocyte-derived membranes, membrane-derived vesicles, or leukocyte-inspired surface ligands, these platforms are designed to improve vascular engagement, synovial localization, joint retention, and payload delivery. Preclinical arthritis studies suggest that LM-NPs can enhance joint accumulation and therapeutic efficacy for small molecules, biologics, and nucleic-acid therapeutics while reducing systemic exposure relative to non-biomimetic nanoparticles or free-drug formulations. However, the current evidence base is stronger for neutrophil-mimetic systems than for macrophage-mimetic or hybrid platforms, and direct head-to-head comparisons remain limited. This review analyzes the design principles, trafficking mechanisms, preclinical evidence, and translational barriers of LM-NPs in autoimmune arthritis, with emphasis on how biomimetic engineering can complement passive inflammatory targeting. We further discuss unresolved challenges related to immunogenicity, manufacturing scalability, reproducibility, regulatory classification, and comparative benchmarking that must be addressed before clinical translation.