Spherical nucleic acid (SNA), as a good gene delivery system, has a good application prospect for transdermal administration in skin disorder treatment. However, most of the traditional SNA core materials are non-degradable materials, so it is worthy of further research. Herein, we report a spherical nucleic acid based on poly-hyaluronic acid (PHA) for the co-delivery of a typical chemotherapeutic drug, doxorubicin (DOX), and an antisense oligonucleotide (ASO) against the tissue inhibitor of metalloproteinases 1 (TIMP-1) for the treatment of hypertrophic scars (HS) which are caused by abnormal fibroblast proliferation. Our study showed that PHA-based SNAs simultaneously bearing TIMP-1 ASO and DOX (termed PHAAD) could significantly promote skin penetration, improve the cellular uptake, and effectively down-regulate the TIMP-1 expression and enhance the cytotoxicity of DOX. Moreover, PHAAD nanoparticles facilitated the apoptosis of hypertrophic scar cells, and reduced the burden and progression of hypertrophic scars in a xenografted mouse model without adverse side effects. Thus, our PHA-based SNA represents a new transdermal delivery vehicle for efficient combinatorial chemo and gene therapy, which is expected to treat various skin disorders.