Therapeutic delivery to inflamed joints remains a critical challenge in rheumatoid arthritis (RA) management due to systemic clearance and nonspecific biodistribution. Within the RA synovial microenvironment, macrophage activation as a central pathogenic mechanism, by exhibit pro-inflammatory M1 polarization, mediating inflammatory progression through sustained secretion of pro-inflammatory cytokines. Removal of M1-phenotype macrophages or their conversion to the M2 phenotype is a promising strategy for the treatment of RA. In this study, asparagus polysaccharides (AP) of white asparagus as a kind of functional foods with therapeutic properties selected as anti-inflammatory agent were encapsulated into liposomes modified withdextran sulfate (DS), a high-affinity ligand for macrophage scavenger receptor-A (SR-A) to construct an actively macrophage-targeted drug delivery system (DS-AP@Lip) for RA targeted therapy. Our results revealed that DS-AP@Lip exhibited a nearly spherical structure with a particle size of 145.2 ± 5.1 nm with low cytotoxicity, high drug loading capacity, good sustained release profile and good stability. The in vitro anti-inflammatory data further showed that DS-AP@Lip were effectively taken up by macrophages with significant anti-inflammatory activity and M2-biased differentiation. In a rat RA model, we found that DS-AP@Lip could preferentially target to macrophages when intravenously administrated and remarkably facilitated AP distribution and retention in inflamed joints. DS-AP@Lip treatment resulted in significant attenuation of synovial inflammation, cartilage erosion, and pro-inflammatory cytokine levels while promoting M2 repolarization. Especially, DS-AP@Lip downregulated the gene expression of p38-MAPK and NF-κB, inhibited the levels of p38-MAPK and NF-κB p65 proteins as well as elevation of the level of iκB protein, indicating that the anti-inflammatory mechanism of DS-AP@Lip should be based on synergistically suppressed NF-κB/MAPK signaling pathways. In conclusion, our work offers a facile approach by utilizing specific receptor-ligand interactions to improve the specific macrophage-targeted ability of the nanocarrier in RA joints and then achieve the precise delivery of AP, enhancing therapeutic efficacy against RA pathogenesis.
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