H₂O₂-activatable hybrid prodrug nanoassemblies as a pure nanodrug for hepatic ischemia/reperfusion injury

Self-assembling prodrugs are able to form stable nanoparticles without additional excipients and therefore have gained increasing interest in the field of drug delivery. As a natural derivative of vitamin A, all-trans retinoic acid (atRA) exerts antioxidant, anti-inflammatory, and immunostimulatory effects. However, the clinical translation of atRA has been hampered by its insufficient therapeutic efficacy. In this work, to fully maximize the therapeutic potential of atRA, we developed delicately designed self-assembling RABA (atRA-based hybrid prodrug) as a hybrid prodrug of atRA and hydroxybenzyl alcohol (HBA). RABA could form nanoassemblies and decompose to release atRA and HBA simultaneously in response to hydrogen peroxide (H₂O₂). In a mouse model of hepatic ischemia/reperfusion (IR) injury, RABA nanoassemblies accumulated in liver preferentially and exerted highly potent antioxidant, anti-inflammatory, and antiapoptotic effects, leading to effective protection of liver from IR injury. RABA nanoassemblies exhibited significantly higher therapeutic efficacy than the combination of equivalent atRA and HBA. Given its H₂O₂-responsiveness, self-assembling and self-immolating behaviors, and cooperative therapeutic actions, RABA nanoassemblies have great potential as a pure nanodrug for hepatic IR injury. This study also provides a new valuable addition in the development of prodrug self-assemblies that will emerge as next generation of drugs.