Purpose A strategy not usually used to improve carrier-mediated delivery of therapeutic enzymes is the attachment of the enzymes to the outer surface of liposomes. The aim of our work was to design a new type of enzymosomes with a sufficient surface-exposed enzyme load while preserving the structural integrity of the liposomal particles and activity of the enzyme. Methods The therapeutic antioxidant enzyme superoxide dismutase (SOD) was covalently attached to the distal terminus of polyethylene glycol (PEG) polymer chains, located at the surface of lipid vesicles, to obtain SOD-enzymosomes. Results The in vivo fate of the optimized SOD-enzymosomes showed that SOD attachment at the end of the activated PEG slightly reduced the residence time of the liposome particles in the bloodstream after IV administration. The biodistribution studies showed that SOD-enzymosomes had a similar organ distribution profile to liposomes with SOD encapsulated in their aqueous interior (SOD-liposomes). SOD-enzymosomes showed earlier therapeutic activity than both SOD-liposomes and free SOD in rat adjuvant arthritis. SOD-enzymosomes, unlike SOD-liposomes, have a therapeutic effect, decreasing liver damage in a rat liver ischemia/reperfusion model. Conclusions SOD-enzymosomes were shown to be a new and successful therapeutic approach to oxidative stress-associated inflammatory situations/diseases.