There has been a progressive interest in the molecular design of polymers and lipids as synthetic carriers for targeting therapeutic mRNA in vivo with the ability to circumvent nuclease attack for treating intractable diseases. Herein, we developed a simple approach to attain one order of magnitude higher nuclease tolerability of mRNA through the formation of polyplex micelles (PMs) by combining ω-cholesteryl (ω-Chol)-poly (ethylene-glycol) (PEG)-polycation block copolymers with mRNA pre-hybridized with cholesterol (Chol)-tethered RNA oligonucleotides (Chol (+)-OligoRNA). Even one or a few short Chol (+)-OligoRNA anchors harboring along the 46-fold longer mRNA strand was sufficient to induce tight mRNA packaging in the PM core, as evidenced by Förster resonance energy transfer (FRET) measurement as well as by a longitudinal relaxation time (T1) measurement using NMR. These results suggest that Chol (+)-OligoRNA on mRNA strand serves as a node to attract ω-Chol moiety of the block copolymers to tighten the mRNA packaging in the PM core. These mRNA loaded PMs showed high tolerability against nuclease attack, and exerted appreciable protein translational activity in cultured cells without any inflammatory responses, achieved by shortening of the length of hybridizing Chol (+)-OligoRNAs to 17 nucleotides. Finally, the Chol (+)-OligoRNA-stabilized PM revealed efficient mRNA introduction into the mouse lungs via intratracheal administration, demonstrating in vivo utility of this formulation.