Copper peroxide/manganese dioxide nanoparticles crosslinked hyaluronan hydrogel for enhanced chemodynamic/photodynamic/photothermal therapy in breast cancer

Therapeutic hydrogels are becoming a promising option of Cancer treatment. However, the simple construction of multifunctional hydrogels under physiological conditions is still a huge challenge. Herein, a chlorin e6 (Ce6)-embedded hyaluronan/CuO₂/MnO₂ nanocomposite hydrogel (Ce6@HHCM) was developed at physiological pH through an innovative mineralization-induced metal-hydrazide coordinative crosslinking technique. The hydrogel exhibited adjustable degradation rate, outstanding mechanical performance, excellent biosuitability, stimulus-responsive behavior, injectability, and self-healing functionality. Upon intratumoral injection in mouse breast Cancer model, weakly acidic and highly reducible tumor microenvironment triggered the decomposition of CuO₂ to Cu⁺, H₂O₂ and O₂ with the help of catalase-like MnO₂, accompanied by both hydrogel breakage and Ce6 release acceleration. The as-generated H₂O₂ and O₂ greatly improved Cu⁺-based chemodynamic therapy and Ce6-mediated photodynamic therapy, respectively, thus yielding a strong Reactive Oxygen Species (ROS, including •OH and ¹O₂) storm. Meanwhile, CuO₂, MnO₂ and disulfide bonds together depleted glutathione to avoid the consumption of ROS. Furthermore, the excellent photothermal heating ability of MnO₂ not only directly ablated Cancer cells but also significantly promoted chemodynamic/photodynamic therapy. This study presents a novel mineralization-driven metal-hydrazide coordination crosslinking approach for fabrication of therapeutic hyaluronan hydrogels and provides a four-pronged ROS-elevation strategy to potentiate topical chemodynamic/photodynamic/photothermal triple therapy in breast Cancer.