To address the cytotoxicity of polyethyleneimine-based siRNA delivery systems and achieve a carrier-drug synergistic anti-inflammatory effect, this study synthesized several sulfated hyaluronan-polyethyleneimine-polyphenol ternary complexes and evaluated their physicochemical and biological potential as siTNF-α delivery carriers. The sulfated hyaluronan-polyethyleneimine-caffeic acid (S-HA-PEI-CA) composite was found to exhibit ideal particle size distribution (1~2 μm), stable microparticle structure, excellent biosafety and strong siTNF-α loading capacity (20 μg/mg). The in vitro experiments demonstrated that S-HA-PEI-CA significantly suppressed the transcription of pro-inflammatory cytokines in LPS-activated RAW264.7 cells. Concurrently, the system markedly upregulated anti-inflammatory arginase-1 (Arg-1) protein expression while inhibiting pro-inflammatory inducible nitric oxide synthase (iNOS) protein production, promoting macrophage transition towards an anti-inflammatory phenotype. Flow cytometry and confocal laser scanning microscopy confirmed S-HA-PEI-CA possessed significant macrophage-targeting capability and achieved efficient siTNF-α delivery via material endocytosis with a gene silencing efficiency of 42.49%. In summary, this delivery carrier not only has high biocompatibility, but also can leverage its inherent anti-inflammatory activity to produce synergistic therapeutic effects, thus further improving the therapeutic efficacy and bringing new ideas for the development of siRNA delivery systems.