Zinc‐Coordinated Lipids: Facilitators for Enhanced mRNA Delivery Efficacy

Abstract The advancement of mRNA therapeutics necessitates more efficient delivery systems. Current clinically advanced lipid nanoparticles (LNPs) primarily bind mRNA through electrostatic interactions, with limited exploration of other intermolecular forces that can benefit multiple delivery processes. Here, we design zinc‐coordinated lipids (Zn‐CL) to formulate LNPs, enabling high mRNA delivery efficacy in vivo. The zinc‐coordinated moieties in ionizable lipids show strong affinity toward phosphate groups, yielding tight yet reversible mRNA encapsulation. In addition, due to the abundance of phosphate groups in biological membranes, Zn‐CL lipids engage them to boost enhanced cellular uptake. Once inside endosomes, competitive binding of zinc‐coordinated moieties to the membranes strengthens endosomal destabilization and weakens Zn‑CL/mRNA interactions, enabling efficient endosomal escape as well as rapid cytosolic mRNA release and resolving the long‑standing paradox between stable encapsulation and efficient release. As a result, zinc coordination introduction simultaneously solves multiple mRNA delivery obstacles, ultimately leading to 29‐fold higher mRNA translation than FDA‐approved SM‐102 LNPs in vivo. Notably, this coordination strategy is extendable to other metal ions, with cobalt‐coordinated lipids facilitating spleen‐targeted mRNA delivery. These findings highlight the substantial potential of metal‐coordinated lipids as a versatile platform for enhancing mRNA therapeutic delivery.