H–NOX proteins are mutated to exhibit improved or optimal kinetic and thermodynamic properties for blood gas O.sub.2 delivery. The engineered H–NOX proteins comprise mutations that impart altered O.sub.2 or NO ligand-binding relative to the corresponding wild-type H–NOX domain, and are operative as physiologically compatible mammalian blood O.sub.2 gas carriers. The invention also provides pharmaceutical compositions, kits, and methods that use wild-type or mutant H–NOX proteins for the treatment of any condition for which delivery of O.sub.2 is beneficial.
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