ZIF-8/doxorubicin nanoparticles camouflaged with Cucurbita-derived exosomes for targeted prostate cancer therapy†

Development of biomimetic drug delivery systems (DDSs) holds great promise to overcome various nanoparticle-associated hindrances in cancer therapy. However, producing biomimetic nanoparticles camouflaged by animal cell-secreted exosomes presents several challenges, including low yield and some ethical considerations. Herein, we designed a biomimetic nanocarrier composed of zeolitic imidazolate framework-8 (ZIF-8) encapsulating doxorubicin (DOX) as the core and a shell of exosome-like nanoparticles (EXO) derived from Cucurbita moschata (CEXO). This design enhances safety and addresses some exosome limitations. The CEXO@ZIF-8/DOX platform was further functionalized with an epithelial cell adhesion molecule (EpCAM) aptamer (Apt-CEXO@ZIF-8/DOX) for targeted delivery to prostate cancer (PC) cells. After investigating the anticancer activity of CEXOs on PC-3 cells, the exosomes were utilized to coat ZIF-8/DOX. The immune evasion capability, cellular uptake, and anticancer effects of nanoplatforms were assessed. Moreover, the in vivo effectiveness of the targeted platform in inhibiting tumor growth and minimizing the adverse effects, was assessed using immunocompromised C57BL/6 mice bearing human PC-3 tumors. Cucurbita exosomes decreased cell viability and induced cell cycle arrest and apoptosis in PC-3 cells without affecting the normal cells. The biomimetic CEXO@ZIF-8/DOX improved immune escaping ability and hemocompatibility. The targeted nanocarrier, with augmented uptake and cellular toxicity in EpCAM-positive PC-3 cells, indicated active targeting efficacy mediated by the EpCAM aptamer. These results were supported by animal experiments that implied the effectiveness of Apt-CEXO@ZIF-8/DOX in inhibiting tumor growth without adverse side effects. This study introduces a novel functional nanocarrier that could potentially revolutionize DDSs by utilizing safer and more biocompatible plant exosomes.