Targeting Mitochondrial Oxidative Stress by Calcium/Copper/Elesclomol Tri-Overloaded Nanocages for Osteosarcoma...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Osteosarcoma (OS) is a 'cold tumor' with low immune cell infiltration, limiting traditional treatment efficacy.
• Existing immunotherapies face challenges due to OS's high immunological tolerance and MTAP gene deletion.
• Targeting mitochondrial oxidative stress presents a novel strategy for OS immunotherapy.

Purpose of the Study:

• To develop a pH-responsive nanoplatform for targeted delivery of calcium, copper, and elesclomol to osteosarcoma mitochondria.
• To induce immunogenic cell death (ICD) and enhance anti-tumor immune responses in OS.
• To investigate the potential of copper-based nanomaterials in osteosarcoma immunotherapy.

Main Methods:

• Construction of calcium/copper/elesclomol (Ca²⁺/Cu²⁺/STA-4783) tri-overloaded nanocages (SACCT NCs).
• pH-responsive drug delivery to mitochondria, promoting H₂O₂ overexpression.
• Catalysis of H₂O₂ by Cu⁺ to generate toxic hydroxyl radicals (•OH) for oxidative stress.
• Activation of dendritic cells (DCs) and CD8⁺ T cells via CRT and NLRP3 pathways.

Main Results:

• SACCT NCs effectively delivered Ca²⁺ and STA-4783 to mitochondria, increasing oxidative stress.
• Copper ions (Cu⁺) catalyzed H₂O₂, inducing ICD in OS cells with minimal cuproptosis.
• Overexpression of CRT and NLRP3 activated the DC-CD8⁺ T cell axis, promoting lymphocyte-mediated immunity.
• Demonstrated pH-responsive biodegradability within the tumor immune microenvironment (TIME).

Conclusions:

• The developed SACCT NCs are effective in inducing immunogenic cell death in osteosarcoma.
• This nanoplatform enhances anti-tumor immune responses by activating the DC-CD8⁺ T cell axis.
• Copper-based nanomaterials show significant promise for osteosarcoma immunotherapy.