A Synergistic Sonosensitive Pyroptosis Nanoactivator for Efficient Lung Adenocarcinoma Therapy.

The critical challenge of apoptosis resistance severely constrains the efficacy of conventional cancer therapies. To address this issue, this study turns to pyroptosis, a lytic cell death pathway, and develops a novel therapeutic strategy by repurposing triptolide (TPL), a natural compound from traditional Chinese medicine (TCM), as a potent pyroptosis inducer. We rationally co-load TPL with the sonosensitizer rose bengal (RB) into a customized covalent organic framework (COF) to construct a synergistic nanoplatform (CRT). The "old drug, new trick" paradigm is potentiated by a nanomaterial-mediated synergistic mechanism: US-triggered reactive oxygen species (ROS) generation from RB orchestrates a dual action, simultaneously inducing direct mitochondrial damage and initiating the controlled release of TPL. This dual action creates a feed-forward loop that drives the progressive amplification of cytotoxic signals from both agents, culminating in the cooperative and robust activation of caspase-3/GSDME-mediated pyroptosis. Consequently, this CRT platform effectively circumvents apoptotic resistance, demonstrating tumor-selective accumulation, potent antitumor efficacy in lung cancer models, and a highly favorable biosafety profile. This work establishes a precise and noninvasive nanomedicine paradigm, highlighting how advanced biomaterial design can unlock the synergistic potential of repurposed drugs for next-generation cancer therapy.