Hydroxy-α-sanshool-loaded adipose-targeted mesoporous silica nanoparticles induce white adipose browning and reduce obesity by activating TRPV1

Obesity has become a global threat to health; however, the available drugs for treating obesity are limited. We investigated the anti-obesity effect of hydroxy-α-sanshool (HAS), an amide derived from the fruit of Zanthoxylum bungeanum, which promotes the management of obesity by triggering the browning of white adipose tissue (WAT) targeting the membrane receptor of transient receptor potential vanilloid 1 (TRPV1). However, HAS easily undergoes configuration transformation and oxidative degradation. The short peptide CKGGRAKDC or adipose-targeting sequence (ATS) binds specifically to prohibitin on the surface of WAT cells and can be used as recognition assembly to enhance adipocyte targetability. Furthermore, mesoporous silica nanoparticles (MSNs) are widely used in drug delivery systems because of their large specific surface area and pore volume. Therefore, HAS-loaded adipose-targeted MSNs (MSNs-ATS) were developed to enhance the adipocyte targetability, safety, and efficacy of HAS, and tested on mature 3T3-L1 cells and obese mouse models. MSNs-ATS showed higher specificity for adipocyte targetability without obvious toxicity. HAS-loaded MSNs-ATS showed anti-obesity effects superior to those of HAS alone. In conclusion, we successfully developed adipocyte-targeted, HAS-loaded MSNs with good safety and anti-obesity effects.