A tumor pH-responsive autocatalytic nanoreactor as a H₂O₂ and O₂ self-supplying depot for enhanced ROS-based...

Combining the internal force-driven chemodynamic therapy (CDT) and the external energy-triggered photodynamic therapy (PDT) holds great promise to achieve an advanced anticancer effect based on reactive oxygen species (ROS). However, the insufficient oxy-substrates supply in tumor microenvironment, like hydrogen peroxide (H₂O₂) and oxygen (O₂), is the Achilles heel that greatly restricts the efficacy of this ROS-based treatment. Herein, the construction of a copper peroxide-based tumor pH-responsive autocatalytic nanoreactor (CESAR), via an albumin-mediated biomimetic mineralization strategy is described. The decoration of human serum albumin endows the nanoreactor good hydrophilicity and biocompatibility, which is highly desired for the metal-based materials. Upon exposure to acidic tumor microenvironment, CESAR presents a pH-triggered disintegration with Cu²⁺, H₂O₂ and O₂ generated instantly. The generated H₂O₂ complements the hyperoxide deficiency and initiates a localized Fenton-like reaction with the assistance of Cu²⁺ for highly toxic hydroxyl radicals (•OH) production for improving CDT. The evolved O₂ gas enables hypoxia relief for enhanced Ce6-mediated PDT. This H₂O₂/O₂ self-supplying strategy significantly amplifies the tumor oxidative damage and gains an optimal treatment outcome, which offers a new paradigm for optimizing the tumor therapeutic options limited by oxide or hyperoxide deficiency, not only for CDT/PDT, but also other oxy-substrates involved strategies. STATEMENT OF SIGNIFICANCE: The shortage of oxy-substrates in the tumor microenvironment remains a great challenge for ROS-based cancer therapy. Herein, we introduce human serum albumin as a scaffold to stabilize copper peroxide nanomaterials for constant production of H₂O₂ and O₂ to enhance chemodynamic/photodynamic therapy. The tumor pH-triggered H₂O₂/O₂ production and Cu²⁺ release are confirmed, assuring the strategy of a highly precise, effective way to destroy tumor without any side effects. This work lends new and exciting insights into the engineering design of autocatalytic oxy-substrates self-supply nanoreactor for overcoming the bottlenecks, like the oxy-substrates deficiency of CDT/PDT and the poor stability of metal peroxides, to achieve highly effective chemodynamic/photodynamic therapy.