Metalamino acid framework (MAF)-mediated macrophage depletion and reprogramming for arthritis treatment

Abstract

Inflammatory M1 macrophages play a crucial role in the pathogenesis of rheumatoid arthritis (RA). However, the simultaneous depletion and reprogramming of M1 macrophages in RA therapy remains a significant challenge. To address this issue, we developed a macrophage-targeting metalamino acid framework (MAF) system with dual functions of methotrexate (MTX) delivery and reactive oxygen species (ROS) clearance. Specifically, Zn^2 + ions and 9-fluorenylmethyloxycarbonyl-modified histidine (Fmoc-H) form a framework structure (pZFH) through coordination. The Fmoc-His-Thr-Lys-Pro-Arg peptide (Fmoc-HTKPR) can be easily doped into this structure at different ratios to modulate its targeting ability. MTX and Pt nanodots are loaded into the system by incorporating MTX during the pZFH preparation process and reducing platinum salts adsorbed on the surface of the pZFH-MTX nanoparticles (NPs). The targeting peptide enhanced the recognition and uptake of NPs by inflammatory macrophages. The release of MTX in response to the acidic inflammatory environment controls macrophage proliferation, while the Pt nanodots eliminated ROS, thereby promoting the polarization of proinflammatory M1 macrophages towards anti-inflammatory M2 macrophages. In an RA model, pZFH-MTX-Pt significantly reduced the expression of proinflammatory cytokines TNF-α and IL-6, alleviated joint swelling, and decreased bone hyperplasia. This system thus provides a synergistic RA treatment strategy that combines chemotherapy and immunotherapy.