Exosome-Coated Boron-Containing Evodiamine Derivative Triggered by Pathology-Specific Reactive Oxygen Species Targets Myofibroblasts to Ameliorate Hypertrophic Scarring

Targeting overactivated myofibroblasts is a potential treatment for hypertrophic scarring. Evodiamine, an indole alkaloid derived from Evodiae fructus, has attracted increasing attention for its antitumor efficacy to inhibit proliferation and promote apoptosis of tumor cells. However, its role on hypertrophic scarring remains unexplored. Hence, we engineered a boronic acid-functionalized evodiamine derivative (BED) triggered by pathology-specific reactive oxygen species (ROS) to target myofibroblasts to ameliorate hypertrophic scarring with minimal toxicity to normal fibroblasts. In vitro experiments presented that BED could be triggered by the increased ROS in myofibroblasts and thus selectively induce apoptosis and suppress proliferation of myofibroblasts, inhibit myofibroblast contraction and migration, and suppress α-SMA and collagen expression. The underlying antiscar mechanism was partly mediated by disrupting microtubules and microfilaments, thereby suppressing the proliferation and contraction of myofibroblasts. To optimize delivery and therapeutic efficacy, the exosome-encapsulated delivery system was further developed, and the results showed that exosomes-coated BED, enhancing BED cellular internalization while protecting BED from extracellular ROS degradation, achieved the optimized therapeutic efficacy of hypertrophic scarring in vivo by targeting myofibroblasts. This approach represents a promising therapeutic strategy for hypertrophic scarring and other fibrotic pathologies.