Complex II inhibitor-loaded hollow piezoelectric nanocarriers potentiate respiration-driven piezocatalytic therapy for malignant pleural effusion.

Malignant pleural effusion (MPE) is a prevalent and refractory terminal complication of advanced malignancies, characterized by a tumor-promoting pleural microenvironment that contributes to rapid disease progression and poor prognosis. To overcome the limitations of transient conventional interventions, we developed a tumor-targeted, pH-responsive gold-core-mediated piezoelectrically enhanced hollow nanoplatform (AhBT@Lipo) enabling self-sustained piezocatalytic therapy driven by endogenous intrapleural pressure fluctuations. The integration of an Au core with a hollow BaTiO3 shell establishes a robust metal-piezoelectric interface, enhancing electromechanical energy conversion and promoting efficient carrier separation. Concurrently, the encapsulated mitochondrial complex II inhibitor Atpenin A5 (AA5) suppresses tumor oxygen consumption and induces endogenous H2O2 accumulation, thereby synergistically amplifying reactive oxygen species (ROS) generation under piezocatalytic activation. In LLC and 4T1 MPE mouse models, intrapleural administration of AhBT∩AA5@Lipo markedly reduced pleural effusion volume and tumor burden, while significantly prolonging survival. Mechanistic investigations revealed that this strategy potentiates oxidative stress, triggers immunogenic cell death, and remodels the tumor immune microenvironment. Overall, this study establishes a physiologically driven and substrate-amplified piezocatalytic therapeutic paradigm, in which metabolic intervention serves to enrich catalytic substrates, introducing a new treatment strategy for MPE and other cavity-associated malignancies.