Self-amplifying RNA (SaRNA) is a burgeoning platform that exploits the replication machinery of alphaviruses such as Venezuelan equine encephalitis (VEE) virus or Sindbis virus (SIN). SaRNA has been used for development of human vaccines, but has not been evaluated for porcine vaccine development. Porcine reproductive and respiratory syndrome virus (PRRSV) causes tremendous economic losses to the worldwide pork industry, but current vaccines trigger delayed neutralizing antibody response and confer only partial protection. Here we first compared two SaRNA systems based on VEE and SIN, and demonstrated that in vitro transcribed VEE-based SaRNA conferred prolonged reporter gene expression and RNA amplification in pig cells with low cytotoxicity, but SIN-based SaRNA imparted evident cytotoxicity and limited gene expression in pig cells. Transfection of VEE-based SaRNA that encodes the major PRRSV antigen dNGP5 (SaRNA-dNGP5) conferred persistent expression for at least 28 days in pig cells. We next complexed SaRNA-dNGP5 with the polyaspartamide block copolymer PEG-PAsp(TEP) to form polyplex nanomicelle with high packaging efficiency and narrow size distribution. The polyplex nanomicelle enabled sustained dNGP5 expression and secretion in vitro. Compared with the commercial PRRS vaccine, nanomicelle delivery of SaRNA-dNGP5 into animal models accelerated the induction of potent neutralizing antibodies with minimal side effects, and elicited stronger IL-4 and IFN-γ responses against homologous and heterologous PRRSV. These properties tackle the problems of current vaccines and implicate the potential of SaRNA-dNGP5 nanomicelle as an effective PRRS vaccine. Chang et al. developed a SaRNA-based vaccine delivered using polyplex nanomicelle to prolong the antigen expression and enhance humoral/cell-mediated immune responses in animal models. Display omitted •VEE SaRNA conferred prolonged gene expression and RNA amplification in pig cells with low toxicity.•VEE SaRNA encoding PRRSV antigen dNGP5 conferred expression for >28 days in pig cells.•SaRNA complexed with polyaspartamide block copolymer formed polyplex nanomicelle with high packaging efficiency.•Nanomicelle delivery of SaRNA-dNGP5 in vivo accelerated the induction of anti-PRRSV neutralizing antibodies.•Nanomicelle delivery of SaRNA-dNGP5 elicited strong cellular immune responses against homologous and heterologous PRRSV.