Dual-organelle–coordinated sonodynamic nanoplatform amplifies immunogenic cell death to drive robust antitumor immunity in cold tumors
10 affiliations
- 1Department of Clinical Laboratory, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 China
- 2Department of radiology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 China
- 3Department of Hepatobiliary surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 China
- 4Department of Emergency, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 China
- 5Department of Gastroenterology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 China
- 6Department of Clinical Laboratory, Pathology and Laboratory Center of the First Affiliated Hospital of Hunan, University of Chinese Medicine, Changsha, 410004 China
- 7Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing, 400038 China
- 8Department of Breast and Thyroid Gland Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 China
- 9College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083 Hunan China
- 10Tumor Immunity Research Center of Hunan Provincial Geriatric Institute, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005 China
Abstract
Immune-excluded “cold” tumors are characterized by dense stromal barriers, limited cytotoxic T-cell infiltration, and insufficient immunogenic cell death (ICD), which collectively restrict the efficacy of immunotherapy. Pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC) represent two of the most refractory cold tumor entities, marked by pronounced desmoplasia and persistent immune exclusion. Here, we report a mitochondria–lysosome dual-organelle–enriched nanoplatform (PT2@GEM NPs) designed to amplify ICD through sonodynamically induced subcellular stress. The organic sonosensitizer PT2 is engineered for stable lysosomal retention via endo–lysosomal trafficking, while cationic structural motifs promote mitochondrial accumulation. Upon ultrasound activation, PT2@GEM NPs generate reactive oxygen species concurrently in lysosomes and mitochondria, inducing lysosomal membrane permeabilization and severe mitochondrial dysfunction, including widespread mitochondrial permeability transition pore opening and loss of membrane potential. As a result, canonical ICD hallmarks are markedly enhanced compared with single-modality treatments. In patient-derived organoids and in murine models of PDAC and TNBC, PT2@GEM NPs combined with ultrasound achieve 60–80% tumor growth inhibition, significantly outperforming chemotherapy or sonodynamic therapy alone. This treatment prolongs survival without evident systemic toxicity. Integrated transcriptomic, metabolomic, and immunological analyses reveal robust activation of inflammatory and innate immune pathways, metabolic rewiring, a 2–3-fold increase in intratumoral CD8⁺ T-cell infiltration, and a 3-fold expansion of effector memory T cells, indicating durable antitumor immune memory. This work establishes a materials-driven sonodynamic chemoimmunotherapy strategy in which rational dual-organelle targeting synchronizes intracellular stress to amplify ICD, convert immune-excluded cold tumors into CD8⁺ T cell–inflamed phenotypes, and provide a translatable nanotechnological approach for the treatment of stromal-rich malignancies.
Graphical abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12951-026-04891-4.
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BibTeX
@article{shao2026dualorganellecoordinated,
title = {{Dual-organelle–coordinated sonodynamic nanoplatform amplifies immunogenic cell death to drive robust antitumor immunity in cold tumors}},
author = {Min Shao and An Xie and Yi Liu and Xu Xu and Qi Yi and Xin Liu and Meina He and Bingyan Zhang and Ya Peng and Feng Huang and Zhonghua Deng and Xiaobing Xie and Youcai Deng and Jianing Yi and Minhuan Lan and Ying Huang and Chaochao Tan},
journal = {Journal of Nanobiotechnology},
year = {2026},
month = aug,
doi = {10.1186/s12951-026-04891-4},
url = {https://doi.org/10.1186/s12951-026-04891-4},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Dual-organelle–coordinated sonodynamic nanoplatform amplifies immunogenic cell death to drive robust antitumor immunity in cold tumors
AU - Min Shao
AU - An Xie
AU - Yi Liu
AU - Xu Xu
AU - Qi Yi
AU - Xin Liu
AU - Meina He
AU - Bingyan Zhang
AU - Ya Peng
AU - Feng Huang
AU - Zhonghua Deng
AU - Xiaobing Xie
AU - Youcai Deng
AU - Jianing Yi
AU - Minhuan Lan
AU - Ying Huang
AU - Chaochao Tan
PY - 2026
DA - 2026/08/08
JO - Journal of Nanobiotechnology
DO - 10.1186/s12951-026-04891-4
UR - https://doi.org/10.1186/s12951-026-04891-4
AB - Immune-excluded “cold” tumors are characterized by dense stromal barriers, limited cytotoxic T-cell infiltration, and insufficient immunogenic cell death (ICD), which collectively restrict the efficacy of immunotherapy. Pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC) represent two of the most refractory cold tumor entities, marked by pronounced desmoplasia and persistent immune exclusion. Here, we report a mitochondria–lysosome dual-organelle–enriched nanoplatform (PT2@GEM NPs) designed to amplify ICD through sonodynamically induced subcellular stress. The organic sonosensitizer PT2 is engineered for stable lysosomal retention via endo–lysosomal trafficking, while cationic structural motifs promote mitochondrial accumulation. Upon ultrasound activation, PT2@GEM NPs generate reactive oxygen species concurrently in lysosomes and mitochondria, inducing lysosomal membrane permeabilization and severe mitochondrial dysfunction, including widespread mitochondrial permeability transition pore opening and loss of membrane potential. As a result, canonical ICD hallmarks are markedly enhanced compared with single-modality treatments. In patient-derived organoids and in murine models of PDAC and TNBC, PT2@GEM NPs combined with ultrasound achieve 60–80% tumor growth inhibition, significantly outperforming chemotherapy or sonodynamic therapy alone. This treatment prolongs survival without evident systemic toxicity. Integrated transcriptomic, metabolomic, and immunological analyses reveal robust activation of inflammatory and innate immune pathways, metabolic rewiring, a 2–3-fold increase in intratumoral CD8⁺ T-cell infiltration, and a 3-fold expansion of effector memory T cells, indicating durable antitumor immune memory. This work establishes a materials-driven sonodynamic chemoimmunotherapy strategy in which rational dual-organelle targeting synchronizes intracellular stress to amplify ICD, convert immune-excluded cold tumors into CD8⁺ T cell–inflamed phenotypes, and provide a translatable nanotechnological approach for the treatment of stromal-rich malignancies. Graphical abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12951-026-04891-4.
SN - 1477-3155
ER -