Microenvironment-responsive piezoelectric nanoreactors integrate O₂ and H₂ generation for efficient tumor sonodynamic...

Sonodynamic therapy (SDT) has emerged as a research hotspot in tumor therapy due to its non-invasiveness, non-toxicity and high penetrability, as it activates sonosensitizers to generate reactive oxygen species (ROS) for tumor cell ablation under ultrasound irradiation. However, its therapeutic efficacy is severely compromised by the rapid electron-hole recombination of sonosensitizers, tumor hypoxia and high intracellular glutathione (GSH) levels in the tumor microenvironment. Herein, we developed a nanoreactor AB@CZP@HO to achieve synergistic antitumor effects of SDT and hydrogen therapy. Based on carbon-doped hollow porous CZ, this material features unique carbon doping and oxygen vacancies that inhibit electron-hole recombination, thus enhancing its piezoelectric coefficient and ultrasound-induced ROS generation capacity. Pt atoms deposited on the CZ surface form CZP, whose catalase-like activity catalyzes the decomposition of intracellular hydrogen H₂O₂ to produce O₂, alleviating tumor hypoxia and providing more substrates for SDT. The loaded ammonia borane with high hydrogen storage capacity enables high-load intratumoral hydrogen delivery and pH-responsive release. The released H₂ disrupts the redox homeostasis and mitochondrial membrane integrity of tumor cells, synergizing with SDT. The surface-modified hyaluronic acid (HA) derivative HO depletes intratumoral GSH via affinity substitution reaction, further boosting SDT efficacy. This design integrates the rational fabrication of piezoelectric materials, tumor microenvironment remodeling and hydrogen therapy synergy, which collectively enhance the therapeutic efficacy of SDT. STATEMENT OF SIGNIFICANCE: This study aims to develop a nanoreactor (AB@CZP@HO) for highly efficient sonodynamic therapy (SDT) of tumors through the fabrication of a highly responsive piezoelectric sonosensitizer, modulation of the tumor microenvironment (TME), and synergy with hydrogen gas therapy. Hydrogen can disrupt the intracellular redox balance and impair the integrity of mitochondrial membranes, thereby enhancing the therapeutic efficacy of SDT and overcoming the limitations of SDT as a monotherapy. This multifunctional nanoreactor integrates multiple functional modules and is expected to provide a novel and effective strategy for tumor SDT, breaking through the limitations of existing therapeutic approaches.