H2O2 self-supplying nanoparticles for chemodynamic and synergistic photodynamic therapy to augment cGAS/STING activation†

Triple negative breast cancer (TNBC) characterized by easy metastasis and poor prognosis is one of the most intractable malignancies. Immunotherapy, as one of the most promising treatments for TNBC, has limited efficacy due to the immunosuppressive tumor microenvironment (ITME). Herein, copper peroxide nanodots (CPN) and chlorin e6 (Ce6) were encapsulated in a liposome with the cinnamaldehyde dimer (CDC) to improve the ITME and enhance anti-tumor activity. To be specific, after endocytosis by cancer cells, Ce6-CPN@CDC released H₂O₂ and Cu²⁺ in the acidic tumor environment. Next, Cu²⁺ was reduced by GSH to Cu⁺, and Cu⁺ catalyzed H₂O₂ to produce ˙OH for chemodynamic therapy (CDT). Meanwhile, under near-infrared laser irradiation, singlet oxygen (¹O₂) can be generated from the released Ce6, exerting a robust photodynamic anticancer effect. In addition, the high ROS-induced ICD and direct DNA damage activated the cGAS-STING pathway, which significantly improved the ITME to amplify the immunostimulatory effect. In vitro and in vivo studies showed that the Ce6-CPN@CDC nanoparticle could realize effective tumor inhibition with minimal toxic side effects. Together, Ce6-CPN@CDC provides a paradigm for combining PDT and CDT to activate immunotherapy and provides a new strategy to improve the efficacy of multimodal synergistic therapy for TNBC.