Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium: Integration of herbal medicine, enzyme engineering, and nanotechnology

Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium (EF) and possess excellent therapeutic effects on various diseases. Encouragingly, in 2022, icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma (HCC) by National Medical Products Administration (NMPA) of China. Moreover, recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects. Nonetheless, both production effi-ciency and clinical applications of epimedium flavonoids have been restrained because of their low content, poor bioavailability, and unfavorable in vivo delivery efficiency. Recently, various strategies, including enzyme engineering and nanotechnology, have been developed to increase productivity and activity, improve delivery efficiency, and enhance therapeutic effects of epimedium flavonoids. In this review, the structure-activity relationship of epimedium flavonoids is described. Then, enzymatic en-gineering strategies for increasing the productivity of highly active baohuoside I and icaritin are dis-cussed. The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized. Finally, the challenges and an outlook on clinical translation of epi-medium flavonoids are proposed.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Xi'an Jiaotong University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

In 2022, icaritin soft capsules were approved by the NMPA of China for the treatment of HCC. However, the low content, poor bioavailability, and unfavorable delivery efficiency of epimedium flavonoids have hampered their production efficiency and clinical applications. Various strategies, including enzyme engineering and nanotechnology, have recently been developed to increase productivity, improve delivery efficiency, and enhance therapeutic effects. This review discusses the structure-activity relationship of epimedium flavonoids, enzymatic engineering strategies, and nanomedicines for overcoming delivery barriers and improving therapeutic effects.