Mitochondria-targeted cuproptosis-driven nanoplatform for synergistic photothermal/chemodynamic therapy and systemic antitumor immunotherapy

Cuproptosis, a recently identified copper-dependent regulated cell death pathway driven by mitochondrial lipoylated protein aggregation, holds considerable promise for cancer therapy. Its clinical translation is constrained by off-target toxicity of free copper ions, inadequate mitochondria-targeted delivery and the immunosuppressive tumor microenvironment. We developed a hyaluronic acid-camouflaged, pH-responsive nanoplatform HACCR for mitochondria-targeted, cuproptosis-driven synergistic therapy and systemic antitumor immunity. The nanoplatform core relies on self-assembled architecture via π-π stacking between copper-metformin carbon dots and immune adjuvant R837, achieving high payload efficiencies 43.6% for CuMCDs and 35.2% for R837. CuMCDs synthesized via one-pot hydrothermal synthesis exhibit intrinsic mitochondria-targeting properties, facilitating precise copper delivery to cuproptosis initiation sites and amplifying pathway activation. They display efficient photothermal conversion under 808 nm laser irradiation, directly inducing tumor cell death while enhancing cuproptosis, chemodynamic therapy and immunogenic cell death. The hyaluronic acid-cinnamaldehyde micelle shell enables CD44-mediated tumor targeting and acidic tumor microenvironment-responsive payload release to mitigate off-target effects. In vitro and in vivo evaluations confirm effective cuproptosis induction, immunosuppressive tumor microenvironment reversal and enhanced dendritic cell maturation and T cell infiltration. Combined with anti-PD-L1 checkpoint blockade, HACCR achieves robust primary tumor eradication and distant metastasis inhibition with favorable systemic biosafety. This work establishes a versatile nanoplatform for cuproptosis-based synergistic cancer immunotherapy, offering insights for clinical translation of copper-dependent cell death strategies.