Homologous Boron Nitride Heterostructure: Piezoelectricity, Catalysis, and Nitric Oxide Release to Reprogram the Tumor Microenvironment for Anticancer

The tumor microenvironment (TME) inherently exhibits treatment resistance, which restrains the therapeutic effect. Here, intracellular piezoelectric catalysis and stepwise nitric oxide (NO) release were integrated to modulate the TME for anticancer therapy. A piezoelectric homologous boron nitride (BN) heterostructure (BN3:1) was prepared, which promotes the piezoelectric character and facilitates the spatial separation of ultrasound (US)-generated charges. The electrons dominate reactive oxygen species (ROS) generation, and the holes also consume endogenous glucose and nicotinamide adenine dinucleotide phosphate (NADPH). The simultaneous reactions of electrons and holes not only facilitate charge separation but also disrupt TME metabolism. In addition, BN3:1 releases NO in response to TME-specific H⁺/H₂O₂. Under US irradiation, increased ROS generation boosts NO release to damage DNA/mitochondria and decompose the extracellular matrix (ECM). Without US, moderate NO release is conducive to vascular normalization, hypoxia relief, and PD-L1 downregulation. Furthermore, intracellular NO microbubbles amplify US imaging contrast, endowing efficient monitoring of NO release <i>in vitro</i> and <i>in vivo</i>. It is the first time employing BN nanosheets as sonosensitizers and NO donors. The synergistic effect grants great anticancer efficiency, which can also arouse an anticancer immune response to further fight against metastasis and recurrence.