An Exosome-Liposome Hybrid Platform for Celastrol Delivery Enhances Anti-Tumor Efficacy in Hepatocellular Carcinoma

Introduction: Celastrol (CEL), a promising agent for HCC treatment, is greatly restricted in clinical use because of its extremely low water solubility and high systemic toxicity. Novel delivery to enhance its therapeutic index is a key challenge. Methods: This study constructed a novel biomimetic hybrid nanodelivery system (CEL-Lipo-Exo) by the fusion of CEL-encapsulated liposome (CEL-Lipo) with exosomes derived from immortalized human mesenchymal stem cells. The in vitro and in vivo physicochemistry, anti-tumor efficacy, and toxicomechanistic properties of the nanoparticles were systematically characterized. Results: The resulting CEL-Lipo-Exo nanoparticle system showed uniform size distribution (100 nm), preserved essential features of exosomes, and high loading capacity (EE75%). In vitro, CELLipo- Exo more efficiently suppressed HCC cell growth and reduced cell migration and invasion, as well as caused greater apoptosis than free CEL and control liposomes. In vivo, the CEL-Lipo-Exo demonstrated the strongest inhibitory activities against tumors and completely abolished free CELinduced systemic toxicity. Discussion: The efficacy of converting a potent but cytotoxic natural compound to an effective nontoxic drug can be enhanced using the exosome-liposome hybrid concept. Utilizing the exosome shell as a biological camouflage, this platform surmounts the major barriers of celastrol for clinical application, thereby suggesting that biomimetic nanomedicine could be a solution for challenging drug candidates. Conclusion: This CEL-Lipo-Exo nanoplatform is a very promising approach for the seeking of "safe and efficient" carriers of celastrol, suggesting an emerging target strategy for HCC therapy.