Macrophage-targeted liposomes as a nano-immunomodulator for rheumatoid arthritis: Harnessing the therapeutic potential of white asparagus polysaccharides

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. Schematic illustration of preparation and therapeutic mechanism against RA of DS-AP@Lip.