Click Lipid Nanoparticles for the Delivery of mRNA to Metabolically Labeled Cancer Cells

Lipid nanoparticle (LNP)-based mRNA delivery has a lot of potential in combating a wide range of diseases, but delivering mRNA to specific cell types continues to be challenging. Despite recent advances in organ and cell specificity, the majority of clinical LNP systems cannot fully release their payload to a targeted site. Incorporating active targeting moieties into LNPs is highly desired to expand nanomedicine applications. In this Letter, we developed LNPs that harness the power of bioorthogonal “click” azide–alkyne chemical reactions. We show that the plasma membranes of cancer cells can be labeled with azide groups by metabolic sugar labeling, and these azide groups can react with dibenzocyclooctyne (DBCO) on LNPs to achieve specific binding. To achieve this, we synthesized new and versatile lipids by functionalizing DBCO groups to phospholipids with or without a poly(ethylene glycol) (PEG) linker. The DBCO lipids were successfully formulated into DBCO-LNPs comprising other standard lipid compounds. When using these DBCO-LNPs to deliver mRNA to metabolically labeled cells, DBCO-LNPs showed a remarkable ability to preferentially deliver mRNA to azide-labeled cells. Removing PEG linkers from DBCO lipids enables better integration and retention in the LNP, and the higher the amount of DBCO lipid, the stronger the targeting effect. This work demonstrates that cell-specific targeting can be achieved utilizing azide–alkyne ″click″ chemistry and could inspire the development of the next generation of LNPs for active cyto-tropic nanomedicines.