Multilayer drug-release microneedles loaded with functional exosomes constitute a multidimensional therapeutic system for the treatment of liver injury

Due to the difficulty in addressing multifactorial complex diseases such as chronic liver injury, we designed multilayer structured microneedles based on multiple pathogenic factors. This study addresses chronic liver injury characterized by high tissue fibrosis and hepatocyte necrosis by utilizing hepatocyte growth factor (HGF) and stem cell exosome solution (HGF@EV) to encapsulate a slow-release antifibrotic drug, nintedanib, within soluble microneedles (H@EV-H/G/N MNP). Applying the patch directly to the skin allows for continuous absorption and gradual degradation of nintedanib in vivo. In vitro experiments showed that nintedanib inhibits M2 polarization, reduces TGF-β secretion, and, in combination with microneedles, suppresses fibroblast proliferation and migration, thus hindering liver fibrosis progression. The regenerative effect of the HGF-loaded stem cell exosome solution led to significant hepatocyte proliferation. Under this dual action, the liver function and quality of life of the mice were effectively improved. By extension, different multilayer microneedles can be constructed to target the pathogenic characteristics of various diseases. This multimodal therapeutic system addresses complex refractory diseases characterized by multiple pathogenic factors.