A novel sono-activatable nanoreactor induces precision intratumoral juglone generation and caspase 3/GSDME-mediated pyroptosis for treatment of bladder cancer

作者：Yuanfeng Zhang, Enguang Yang, Xinyu Zhang, Yibo Shi, Guangrui Fan, Yuhan Wang, Junqiang Tian, Hanzhang Wang, Zhilong Dong, Ying-Ru Wang, Liang Cheng, Zhi‐Wen Zhao, Yonghai Zhang, Baodui Wang, Zhiping Wang · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03855-4 · 被引用次数：2 · 研究领域：Nanoplatforms for cancer theranostics、Ultrasound and Hyperthermia Applications、Inflammasome and immune disorders

Juglone, a natural naphthoquinone compound, exhibits potent anticancer activity but faces clinical limitations due to poor solubility, low bioavailability, and systemic toxicity. While tumor microenvironment-responsive drug activation strategies offer a promising solution, achieving precise spatial control over the conversion of non-toxic precursors into cytotoxic agents remains a significant challenge. We developed DHN@Pt/PtMBCPsNSs, a platinum (Pt)-methylene blue (MB)- based nanoscale sonosensitizer, to enable ultrasound-triggered on-demand juglone synthesis within tumors. The system was evaluated in bladder cancer models including cell lines, patient-derived organoids (PDOs) and patient-derived tumor xenograft (PDX) models, assessing tumor uptake, intracellular distribution, hypoxia modulation (“H 2 O 2 -O 2 -¹O 2 ” cascade), oxidative stress markers (SOD, GSH, MDA, GSSG), and cell death pathways (apoptosis/pyroptosis). Transcriptome sequencing was performed to elucidate molecular mechanisms. DHN@Pt/PtMBCPsNSs were internalized by UMUC-3 and T24 cells and primarily accumulated within the mitochondrial compartments. The platinum-based components catalytically exhausted GSH via redox cycling. DHN@Pt/PtMBCPsNSs triggered the production of O 2 and ¹O 2 after local US irradiation, alleviating hypoxia and selectively converting dihydroxynaphthalene (DHN) to juglone in tumors, which reducing the systemic toxicity of juglone. The nanosystem further disrupted cellular redox balance...