Engineered ε-decalactone lipomers bypass the liver to selectively in vivo deliver mRNA to the lungs without targeting ligands.

RNA drugs hold real potential for tackling devastating diseases that are currently resistant to small molecule drugs or monoclonal antibodies. However, since these drugs are unstable in vivo and unable to pass through cellular membranes their clinical realization is limited by their successful delivery to target sites. Herein we report on the design of a combinatorial library of polyester lipomers based on the renewable monomer, ε-decalactone (ε-DL), via organocatalytic ring-opening polymerization for mRNA delivery. The ε-DL lipomers showed a surprisingly efficient ability to target the lungs upon intravenous administration. Interestingly, most of the lipomers achieved functional EGFP expression in the lungs, while minimally transfecting hepatocytes and splenic cells. This simple approach for the design of biodegradable materials has the potential for the clinical translation of genetic medicines for the treatment of lung diseases.