Organophosphorus compounds (OPC’s) represents highly dangerous substances causing multiple pathogenesis. Thus development of antidote and protective modalities acting on OPC’s is necessary. To obtain such modality, a genetically modified OPH containing hexahistidine tag on the N-terminus of protein globule (His6-OPH) was used. Complexing the enzyme with different block polyanions led to stable non-immunogenic nano-formulation (nano-OPH) with a median size 50±20 nm. Nano-OPH displays long circulation in blood (at least 17 h) after intravenous, intraperitoneal and intramuscular administrations, and overall has very good bioavailability (up to 30%). Nano-OPH administered in white Sprague Dawley rats 1 h before intoxication provided perfect protection against OPC (Paraoxon). Thus the protection ratio (ratio of LD50 of protected animals to LD50 of non-protected animals) was 5.8±0.2 at nano-formulation dose 2500±190 U/kg 1 h pre exposure. Moreover, nano-OPH acted as an antidote resulting in complete survival of animals upon administering 1 min post exposure 1070±60 U/kg of nano-OPH to rats given 4.9×LD50 (4.4×LD100) of Paraoxon.