Purpose: Psoriasis is a chronic and recurrent inflammatory dermatitis characterized by T cell imbalance and abnormal keratinocyte proliferation. MicroRNAs (miRNAs) hold promise as therapeutic agents for this disease; however, their clinical application is hindered by poor stability and limited skin penetration. This study demonstrates the utilization of Framework Nucleic Acid (FNA) for the topical delivery of miRNAs in psoriasis treatment. Methods: By utilizing miRNA-125b as the model drug, FNA-miR-125b was synthesized via self-assembly. The successful synthesis and stability of FNA-miR-125b in bovine fetal serum (FBS) were verified through gel electrophoresis. Subsequently, flow cytometry was employed to investigate the cell internalization on HaCaT cells, while qPCR determined the effects of FNA-miR-125b on cellular functions. Additionally, the skin penetration ability of FNA-miR-125b was assessed. Finally, a topical administration study involving FNA-miR-125b cream on imiquimod (IMQ)-induced psoriasis mice was conducted to evaluate its therapeutic efficacy. Results: The FNA-miR-125b exhibited excellent stability, efficient cellular internalization, and potent inhibition of keratinocyte proliferation. In the psoriasis mouse model, FNA-miR-125b effectively penetrated the skin tissue, resulting in reduced epidermal thickness and PASI score, as well as decreased levels of inflammatory cytokines.