Nitroxide Polymer Encapsulating Triptolide for Safe and Effective Small Cell Lung Cancer Therapy by Targeting Energy Metabolism and Pyroptosis.

Small cell lung cancer (SCLC) is highly aggressive neuroendocrine tumor with a paucity of effective therapeutic option. Triptolide (TP), a natural diterpenoid triepoxide, exhibits potent antitumor activities, yet its efficacy and underlying mechanisms in SCLC remain largely undefined. Here, we demonstrate that TP effectively inhibits cell viability across all molecular subtypes of SCLC, with greater potency than in nonsmall cell lung cancer. Mechanistically, TP transcriptionally represses hexokinase 1 and 2 (HK1/2), thereby disrupting the glycolysis-TCA-OXPHOS axis and resulting in ATP depletion. Furthermore, TP suppresses PI3K-Akt and MAPK proliferative signaling, induces cell cycle arrest, triggers mitochondrial membrane potential collapse, and activates Caspase-3-dependent cleavage of Gasdermin E (GSDME), culminating in pyroptotic cell death. Genetic ablation of GSDME markedly attenuates TP‑induced cytotoxicity in vitro and in vivo. To overcome the clinical limitations of poor solubility and systemic toxicity associated with TP, we encapsulated it into a nitroxide polymer nanocarrier, PNO-PSA to generate PNO-PSA@TP. This nanomedicine maintains potent anti‑SCLC activity in vitro, while significantly enhancing tumor suppression in both subcutaneous and GEMM SCLC mouse models. Importantly, PNO‑PSA@TP drastically reduced TP‑induced hepatotoxicity, nephrotoxicity, and testicular damage, effectively preserving male fertility. Notably, we found that PNO‑PSA encapsulation mitigates TP‑induced ferroptosis in normal tissues, thereby reducing systemic toxicity. Collectively, our findings identify TP as a broad-spectrum anti-SCLC agent acting via energy metabolic disruption and GSDME-dependent pyroptosis, and establish PNO-PSA@TP as a safer and more effective translational candidate for SCLC treatment.