Cucumber‐Derived Extracellular Vesicle‐Functionalized Metal‐Organic Frameworks for Enhanced Photodynamic Therapy of Hypertrophic Scars

Abstract Photodynamic therapy (PDT) with noninvasiveness and high safety has emerged as a promising therapeutic approach for the management of hypertrophic scars (HS). However, the low transdermal delivery and overexpressed levels of intracellular glutathione (GSH) severely hinder its therapeutic effectiveness. Herein, a multifunctional biomimetic nanoplatform (NDs@EV‐RGD) composed of arginine‐glycine‐aspartic acid (RGD)‐modified cucumber‐derived extracellular vesicles (EVs) and copper‐based metal‐organic framework nanodots (Cu‐MOF NDs) is designed for PDT‐mediated HS treatment. The EVs with low Young's modulus exhibit excellent deformability which endow NDs@EV‐RGD with the capacity to overcome the compact stratum corneum barrier, thereby significantly improving their transdermal delivery efficiency. Notably, the RGD targeting peptide displays specific binding to α1β1 integrin on the fibroblast membranes within HS, leading to the high accumulation efficiency of NDs@EV‐RGD at the HS site. Under near‐infrared laser irradiation, NDs@EV‐RGD efficiently generates abundant reactive oxygen species, inducing the apoptosis of excessively proliferated fibroblasts. Moreover, Cu‐MOF NDs interact with the local GSH, leading to GSH depletion and a significant enhancement in PDT efficacy. Furthermore, NDs@EV‐RGD demonstrates a remarkable therapeutic effect in improving the appearance of HS in a rabbit ear HS model, promoting the apoptosis and remodeling of collagen fibers. Therefore, this work provides a promising biomimetic platform for HS treatment.