Targeting Mitochondrial Oxidative Stress by Calcium/Copper/Elesclomol Tri-Overloaded Nanocages for Osteosarcoma Immunotherapy via Immunogenic Cell Death
Guangyao Jiang, Fangming Zhang, Ziyi Wu, Xianghong Zhang, Jingxia Xu, Zihe Peng, Guofeng Li, Guanghui Zhu, Xing Wang, Wensheng Xie
Abstract
Osteosarcoma (OS) immunotherapy offers a solution to overcome the limitations of traditional treatments. However, OS is a “cold tumor” due to deletion of the MTAP gene and sparse infiltration of immune cells, exhibiting high immunological tolerance. Here, we construct calcium/copper/elesclomol (Ca 2+ /Cu 2+ /STA-4783) tri-overloaded nanocages (SACCT NCs) to target mitochondrial oxidative stress and induce immunogenic cell death (ICD) for OS immunotherapy. In this pH-responsive nanoplatform, Ca 2+ and STA-4783 are codelivered to mitochondria, promoting H 2 O 2 overexpression via the TCA cycle and SOD1. Subsequently, Cu + released from SACCT NCs effectively catalyzes H 2 O 2 into toxic •OH, inducing oxidative stress damage and mitochondrial dysfunction rather than triggering cuproptosis (weak cuproptosis). Meanwhile, increased Cu + levels from transmembrane transport by CTR1 and ATP7A/B enhance intracellular oxidative stress, resulting in the ICD of OS cells. Finally, overexpression of CRT and NLRP3 activates the DCs–CD8 + T cell immune response axis through the lymphocyte-mediated immunity pathway, enabling effective immunotherapy. Considering the in vivo pH-responsive biodegradability in the tumor immune microenvironment (TIME), our study has provided an impetus for the design and preparation of copper-based nanomaterials, which are efficacious in OS immunotherapy.