The combination of photothermal therapy (PTT) and gene therapy (GT) has attracted intense interest in cancer treatment. However, the lack of long circulation and active tumor targeting reduces the therapeutic efficacy of complementary PTT/GT. In this work, hyaluronic acid (HA)-cloaked gold nanorods-PGED (prepared by ring-opening of polyglycidyl methacrylate (PGMA) with ethylenediamine (ED))/pDNA (AP/pDNA-HA) complexes were prepared to achieve long circulation and tumor targeting for photoacoustic imaging (PAI)-guided synergistic PTT/GT. Gold nanorods endow the complexes with photothermal effect and PAI function. Benefiting from the HA cloak, the AP/pDNA-HA complexes exhibit excellent stability, biocompatibility, long circulation behavior and active targeting. In addition, the pH-responsive characteristic of the Schiff base bonds helps the AP/pDNA-HA complexes to effectively escape from the endosome/lysosome. The antioncogene p53 was employed to investigate the gene transfection efficiency of the delivery system both in vitro and in vivo. The superiority of synergistic PTT/GT is established in a mouse 4T1 breast tumor model. The current study provides a facile strategy for constructing multifunctional gene delivery systems with long circulation and tumor targeting features, which can achieve effective imaging-guided synergistic tumor treatment.