Abstract: Efficient silencing of tumor necrosis factor-α (TNF-α) is of great significance for acute inflammatory disease therapy. However, the immunogenicity and in-vivo accumulation toxicity of existing siRNA delivery systems have severely limited their clinical applications. To address this issue, this study constructed a sulfated hyaluronan-polyethyleneimine-polyphenol conjugate with both high biocompatibility and anti-inflammatory potential, and systematically evaluated its comprehensive performance as a siTNF-α delivery carrier. First, this study prepared a series of sulfated hyaluronan-polyethyleneimine-polyphenol conjugate microparticles and characterized the physicochemical properties, biosafety and drug-loading efficiency of each material. Through comparative analysis, the sulfated hyaluronan-polyethyleneimine-caffeic acid conjugate (S-HA-PEI-CA) exhibited a uniform particle size distribution (1-2 μm), and high siTNF-α loading capacity (20 μg/mg). Besides, the microparticles effectively regulate the phenotypic polarization of LPS-induced RAW264.7 cells by significantly inhibiting the mRNA expression of IL-1β, IL-6, and TNF-α (62.15%, 81.24% and 33.14% respectively). Meanwhile, it remarkably up-regulated the expression of Arg-1 and down-regulated the expression of iNOS, promoting the transformation of macrophages towards the anti-inflammatory phenotype. Moreover, S-HA-PEI-CA exhibited high macrophage targeting capability, and efficiently delivered siTNF-α to the cell (with a gene silencing efficiency of 42.49%). In summary, this carrier successfully overcomes the immunogenicity limitations of conventional delivery systems, providing an innovative solution for balancing the targeted delivery and biosafety issues in inflammatory disease therapy.