Abstract Lipid nanoparticles (LNPs) are clinically advanced small interfering RNA (siRNA) carriers, which can prevent the breakdown of siRNA during delivery and deliver siRNA into the cytoplasm to down‐regulate the target gene. However, clinical LNPs are limited to the liver, and enhancing extrahepatic targeting is vital to expand the application of LNPs in vivo. Here, zwitterionic polymer LNPs (ZP‐LNPs) are assembled with the zwitterionic polymer polycarboxybetaine (PCB) modified 1,2‐dimyristoylglycerol (DMG) lipid DMG‐PCB n can selectively deliver siRNA to liver and lung, respectively. Three libraries with 90 ZP‐LNPs are established by adjusting the degree of polymerization of DMG‐PCB n , the molar ratio of lipids, and the mass ratio between lipids and siRNA. Physicochemical and in vivo biodistribution results show that B4‐3@siRNA and B5‐1@siRNA with high siRNA encapsulation efficiency (&gt;85%) achieve targeted siRNA delivery to the liver and lung, respectively. The mechanism findings indicate that pKa and protein corona are essential to determine the in vivo fate of ZP‐LNPs and tendency for specific organs. Importantly, these two ZP‐LNPs with siTNF‐α can effectively reduce the levels of tumor necrosis factor α (TNF‐α) in mice with hepatic inflammation and pulmonary inflammation, respectively, indicating their promising application for the treatment of diseases associated with liver and lung.

Zwitterionic Polymer Lipid Nanoparticles Enabling Selective Organ Targeting Delivery of Small Interfering RNA for the Treatment of Hepatic and Pulmonary Inflammation