Celastrol loaded nanocomplex for painless tumor therapy via YAP inhibition

Cancer-related pain is prevalent and severely impairs patients' quality of life. However, conventional cancer therapies primarily target tumor cell destruction, often overlooking the management of cancer pain. Thus, there is an immediate necessity to develop therapeutic agents that can both suppress tumor growth and alleviate cancer pain. In this study, we report a celastrol (CEL)-based nanocomposites (PDA-BSA-MnO₂-CEL) for pain-less cancer immunotherapy. Results from in vitro and in vivo experiments demonstrate the efficacy and mechanism of the nanocomposites in pain-less immunotherapy. MnO₂ and CEL induce immunogenic cell death (ICD), mediating immunotherapy. Additionally, CEL significantly reduces the secretion of the immunosuppressive factor Yes-associated protein (YAP) within the tumor microenvironment, thereby enhancing the efficacy of immunotherapy. The downregulation of YAP leads to reduced expression of vascular endothelial growth factor (VEGF), inhibiting tumor growth and decreasing activation of the pain-associated VEGF receptor 1 (VEGFR1), thus providing an analgesic effect. Moreover, CEL reduces inflammatory pain by lowering levels of inflammatory factors in tumors. The design of this nanocomposites system integrates immunotherapy with cancer pain inhibition, offering a novel approach to patient-centered tumor therapy.