Gout is a disease caused by hyperuricemia, characterized by inflammation reactions triggered by macrophage polarization. Colchicine is a commonly used drug for gout treatment, but its mechanism of action remains unclear. The aim of this study was to investigate the regulatory effect of colchicine on macrophage polarization to enhance the therapeutic effectiveness against gout inflammation. To accomplish this, a mouse model was established, and peripheral blood mononuclear cell samples were collected. Single-cell RNA sequencing was employed to reveal cellular heterogeneity and identify key genes. Molecular docking and experimental validation were performed to confirm the binding between the key genes and colchicine. Lentiviral intervention and biochemical indicator detection were conducted to assess the impact of key genes on gout mice. Additionally, the therapeutic effect of colchicine incorporated into neutrophil membrane-coated nanoparticles was investigated. The study found that macrophage polarization plays a critical role in gout, and AHNAK was identified as the key gene through which colchicine affects macrophage polarization. Lentiviral intervention to decrease AHNAK expression was shown to alleviate joint swelling in gout mice and regulate macrophage polarization. Colchicine encapsulated in R4F peptide-modified neutrophil membrane-coated Pluronic F127 nanoparticle (R4F-NM@F127) nanocarriers inhibited M1 macrophage polarization, induced M2 macrophage polarization, alleviated gout, and minimized toxicity to normal tissues. Colchicine suppressed M1 macrophage polarization and induced M2 macrophage polarization by binding to AHNAK protein, thereby alleviating gout. Colchicine incorporated into R4F-NM@F127 nanocarriers can serve as a targeted therapeutic drug to regulate macrophage polarization, alleviate gout, and reduce toxicity to normal tissues.