Porcine reproductive and respiratory syndrome (PRRS) is one of the major causes of economic burden to the swine industry world-wide. Currently, we lack cross-protective killed PRRS virus (PRRSV) vaccine to effectively control the disease outbreaks. To potentiate the efficacy of killed PRRSV vaccine, we entrapped UV killed PRRSV antigens in poly(lactide-co-glycolide) (PLGA) nanoparticles and co-administered intranasally twice with a potent mucosal adjuvant, Mycobacterium tuberculosis whole cell lysate (M. tb WCL). Our results indicated that, PLGA nanoparticle-entrapped killed PRRSV vaccine adjuvanted with unentrapped M. tb WCL elicited better cross-protective immunity to a virulent heterologous PRRSV challenge. Clinically, immunized virus challenged pigs were free from PRRS symptoms, and immune correlates of protection at both mucosal and systemic sites comprises of: (i) significantly increased levels of PRRSV specific IgG and IgA antibody titers with enhanced avidity and virus neutralizing antibody titers; (ii) complete clearance of viremia and replicating PRRSV from the lungs; (iii) enhanced frequency of IFN-γ secreting cells in the lungs compared to other test groups. Results of our study are having a great promise towards development of a better cross-protective killed PRRSV vaccine to effectively control PRRS outbreaks in pigs. This project was supported by National Pork Board, USDA PRRS CAP2 and OARDC OSU to RG.