Engineering H₂O₂ and O₂ Self‐Supplying Nanoreactor to Conduct Synergistic Chemiexcited Photodynamic and Calcium‐Overloaded Therapy in Orthotopic Hepatic Tumors

Photodynamic therapy (PDT) is traditionally ineffective for deeply embedded tumors due to the poor penetration depth of the excitation light. Chemiluminescence resonance energy transfer (CRET) has emerged as a promising mode of PDT without external light. To date, related research has frequently used endogenous hydrogen peroxide (H₂ O₂ ) and oxygen (O₂ ) inside the solid tumor microenvironment to trigger CRET-mediated PDT. Unfortunately, this significantly restricts treatment efficacy and the development of further biomedical applications because of the limited amounts of endogenous H₂ O₂ and O₂ . Herein, a nanohybrid (mSiO₂ /CaO₂ /CPPO/Ce6: mSCCC) nanoparticle (NP) is designed to achieve synergistic CRET-mediated PDT and calcium (Ca²⁺ )-overload-mediated therapy. The calcium peroxide (CaO₂ ) formed inside mesoporous SiO₂ (mSC) with the inclusion of the chemiluminescent agent (CPPO) and photosensitizer (Ce6) self-supplies H₂ O₂ , O₂ , and Ca²⁺ allowing for the subsequent treatments. The Ce6 in mSCCC NPs is excited by chemical energy in situ following the supply of H₂ O₂ and O₂ to produce singlet oxygen (¹ O₂ ). The nanohybrid NPs are coated with stearic acid to avoid decomposition during blood circulation through contact with aqueous environment. This nanohybrid shows promising performance in the generation of ¹ O₂ for external light-free PDT and the release of Ca²⁺ ions for Ca²⁺ -overloaded therapy against orthotopic hepatocellular carcinoma.