Drug delivery carriers such as lipid nanoparticles (used in mRNA COVID vaccines), viral vectors (used in gene therapy), polymeric nanoparticles (used in long-acting medications and cancer drugs), and liposomes (used in chemotherapy to encapsulate toxic drugs) can improve the effectiveness of many types of treatments and vaccines.

However, delivery carriers are prone to being rapidly cleared by the body after administration, leading to an extremely low drug concentration in target tissues. For instance, the effective delivery dose of existing nanomedicines that reaches tumors is less than 0.7% of the total dose, restricting therapeutic efficacy. Unfortunately, scientists have been unsure how to improve the delivery efficiency of these carriers.

Now, research led by Profs. WANG Yucai, ZHU Shu, and JIANG Wei from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences, has for the first time uncovered the fundamental mechanism underlying the body’s non-specific clearance of drug delivery carriers by identifying a gut–liver immune regulatory axis maintained by intestinal commensal bacteria and the intestinal endocrine system.

The study was published in Science on March 19.

Using a mouse model, the researchers found that the tumor delivery efficiency of various delivery carriers—including polymeric nanoparticles, lipid nanoparticles, and oncolytic adenoviruses—was significantly improved after clearing intestinal commensal bacteria. Such enhanced delivery efficiency may translate into improved therapeutic effects in tumor chemotherapy, oncolytic virus therapy, and protein replacement therapy.

In addition, researchers found that the efficiency of multi-organ gene delivery and somatic cell editing was also greatly increased, since the number of delivery carriers circulating in the blood increased significantly.

To unravel the underlying mechanism, the researchers developed a quantitative analysis system for single-cell morphology and carrier interaction behavior based on intravital imaging. This system confirmed that intestinal bacteria make Kupffer cells—a type of immune cell in the liver—more aggressive at clearing drug carriers. In contrast, when intestinal bacteria were removed, Kupffer cells became much less active in taking up drug carriers, with their uptake capacity reduced by as much as 70%.

Furthermore, researchers clarified that intestinal epithelial cells were the core hub for sensing bacterial signals and regulating liver immunity, with serotonin secreted by the intestinal endocrine system acting as the key messenger molecule linking intestinal bacteria and the liver immune system.

This study outlines for the first time the complete gut–liver immune regulatory axis: intestinal commensal bacteria activate the intestinal epithelial endocrine system to promote serotonin secretion; serotonin then activates hepatic Kupffer cells, enhancing their phagocytic capacity for delivery carriers, which in turn impairs carrier circulation and reduces delivery efficiency.

Experiments verified that intervening in this serotonin pathway or restricting tryptophan intake through dietary regulation—since tryptophan is the precursor of serotonin—can both significantly inhibit Kupffer cells from clearing drug delivery carriers. This intervention increases tumor delivery efficiency by two to three times and target tissue gene editing efficiency by 10–15 times, achieving remarkable improvements in various therapeutic models.

In summary, this study offers a means of significantly improving the delivery efficiency and therapeutic effectiveness of tumor-targeted therapy, mRNA therapy, gene editing, and other treatments.