Ultrasound-Responsive Lipid Nanosonosensitizers with Size Reduction and NO Release: Synergistic Sonodynamic-Chemo-Immunotherapy for Pancreatic Tumors
Leyi Fang
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorWenhui Zeng
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorYili Liu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorYinxing Miao
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorChunmei Lu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorZhonghan Xu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorSensen Zhou
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorQi Xue
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorYitong Xu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorProf. Xiqun Jiang
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorProf. Jingjuan Xu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorCorresponding Author
Prof. Yan Zhang
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
E-mail: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Prof. Deju Ye
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
E-mail: [email protected]; [email protected]
Search for more papers by this authorLeyi Fang
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorWenhui Zeng
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorYili Liu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
These authors contributed equally to this work.
Search for more papers by this authorYinxing Miao
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorChunmei Lu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorZhonghan Xu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorSensen Zhou
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorQi Xue
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorYitong Xu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorProf. Xiqun Jiang
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorProf. Jingjuan Xu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
Search for more papers by this authorCorresponding Author
Prof. Yan Zhang
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
E-mail: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Prof. Deju Ye
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023 China
E-mail: [email protected]; [email protected]
Search for more papers by this authorAbstract
Pancreatic cancer (PC) remains difficult to treat due to its dense extracellular matrix (ECM), immunosuppressive tumor microenvironment (TME), and deep-seated anatomy. To address these challenges, we developed IR&ZnPc@LNP-NO, an ultrasound (US)-responsive lipid nanosonosensitizer that synergizes sonodynamic therapy (SDT), chemotherapy, and immunotherapy for orthotopic PC. IR&ZnPc@LNP-NO undergoes three key US-activated responses: 1) size reduction, 2) controlled release of irinotecan (IR) and nitric oxide (NO), and 3) generation of reactive oxygen species (ROS). Under low-dose US, IR&ZnPc@LNP-NO reduces in size (from ∼120 to ∼40 nm), enhancing tumor penetration, and releases NO to remodel the TME by normalizing vasculature and degrading ECM. This enhances nanosonosensitizers accumulation and cytotoxic T cells (CTLs) infiltration. High-dose US irradiation triggers the generation of cytotoxic ROS, which, in combination with IR-mediated chemotherapy, induces immunogenic cell death (ICD) and enhances antitumor immunity. Additionally, combining IR&ZnPc@LNP-NO with PD-L1 antibody (αPD-L1) immunotherapy significantly prolongs survival in orthotopic PC models. The cascade strategy—size reduction, TME remodeling, and multimodal therapy—effectively overcomes stromal and immunosuppressive barriers, offering a robust platform for treating deep-seated PC.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ange202507388-sup-0001-SuppMat.docx42.3 MB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1R. L. Siegel, K. D. Miller, H. E. Fuchs, A. Jemal, CA Cancer J. Clin. 2022, 72, 7–33.
- 2Z. I. Hu, E. M. O'Reilly, Nat. Rev. Gastro. Hepat. 2024, 21, 7–24.
- 3C. J. Halbrook, C. A. Lyssiotis, M. Pasca di Magliano, A. Maitra, Cell 2023, 186, 1729–1754.
- 4E. Hessmann, S. M. Buchholz, I. E. Demir, S. K. Singh, T. M. Gress, V. Ellenrieder, A. Neesse, Physiol. Rev. 2020, 100, 1707–1751.
- 5A. Gupta, D. Laheru, Ann. Oncol. 2023, 34, S921.
- 6M. Weniger, K. Honselmann, A. Liss, Cancers 2018, 10, 316.
- 7G. Milano, F. Innocenti, H. Minami, Cancer Sci. 2022, 113, 2224–2231.
- 8A. H. Morrison, K. T. Byrne, R. H. Vonderheide, Trends Cancer 2018, 4, 418–428.
- 9C.-K. Looi, F. F.-L. Chung, C.-O. Leong, S.-F. Wong, R. Rosli, C.-W. Mai, J. Exp. Clin. Canc. Res. 2019, 38, 162.
- 10X. Liu, N. Ye, S. Liu, J. Guan, Q. Deng, Z. Zhang, C. Xiao, Z. y. Ding, B. x. Zhang, X. p. Chen, Z. Li, X. Yang, Adv. Sci. 2021, 8, 2100233.
- 11E. Nestoros, A. Sharma, E. Kim, J. S. Kim, M. Vendrell, Nat. Rev. Chem. 2025, 9, 46–60.
- 12S. Li, W. Zhang, R. Xing, C. Yuan, H. Xue, X. Yan, Adv. Mater. 2021, 33, 2100595.
- 13Y. Wang, H. Shen, Z. Li, S. Liao, B. Yin, R. Yue, G. Guan, B. Chen, G. Song, J. Am. Chem. Soc. 2024, 146, 6252–6265.
- 14W. Huang, Y. Yang, D. Ye, Chin. J. Chem. 2023, 41, 2382–2399.
- 15Y. Chen, B. Yin, Z. Liu, H. Wang, Z. Fu, X. Ji, W. Tang, D. Ni, W. Peng, Nano Res. 2022, 15, 6340–6347.
- 16L. Wang, J. Li, Y. Zheng, Y. Li, Q. Zhu, J. Cao, L. Sun, Chem. Eng. J. 2025, 507, 160180.
- 17Y. Liu, H. Wang, M. Ding, W. Yao, K. Wang, I. Ullah, E. Bulatov, Y. Yuan, Nano Lett. 2024, 24, 8741–8751.
- 18K. Zhu, J. Wang, Z. Wang, Q. Chen, J. Song, X. Chen, Angew. Chem. Int. Ed. 2025, 64, e202422278.
- 19D. Li, Y. Yang, D. Li, J. Pan, C. Chu, G. Liu, Small 2021, 17, 2101976.
- 20M. Zhang, D. Sun, H. Huang, D. Yang, X. Song, W. Feng, X. Jing, Y. Chen, Adv. Mater. 2024, 36, 2409663.
- 21X. Lin, J. Song, X. Chen, H. Yang, Angew. Chem. Int. Ed. 2020, 59, 14212–14233.
- 22Y. Li, W. Chen, Y. Kang, X. Zhen, Z. Zhou, C. Liu, S. Chen, X. Huang, H.-J. Liu, S. Koo, N. Kong, X. Ji, T. Xie, W. Tao, Nat. Commun. 2023, 14, 6973.
- 23X. Qian, Y. Zheng, Y. Chen, Adv. Mater. 2016, 28, 8097–8129.
- 24Z. Jiang, W. Xiao, Q. Fu, J. Controlled Release 2023, 361, 547–567.
- 25M. Li, Y. Liu, Y. Zhang, N. Yu, J. Li, Adv. Sci. 2023, 10, 2305150.
- 26L. Liu, J. Zhang, R. An, Q. Xue, X. Cheng, Y. Hu, Z. Huang, L. Wu, W. Zeng, Y. Miao, J. Li, Y. Zhou, H. Y. Chen, H. Liu, D. Ye, Angew. Chem. Int. Ed. 2023, 62, e202217055.
- 27J. Chen, H. Luo, Y. Liu, W. Zhang, H. Li, T. Luo, K. Zhang, Y. Zhao, J. Liu, ACS Nano 2017, 11, 12849–12862.
- 28J. Li, N. Yu, D. Cui, J. Huang, Y. Luo, K. Pu, Angew. Chem. Int. Ed. 2023, 62, e202305200.
- 29F. Yang, J. Lv, W. Ma, Y. Yang, X. Hu, Z. Yang, Small 2024, 20, 2402669.
- 30N. Tao, H. Li, L. Deng, S. Zhao, J. Ouyang, M. Wen, W. Chen, K. Zeng, C. Wei, Y.-N. Liu, ACS Nano 2022, 16, 485–501.
- 31J. O. Lundberg, E. Weitzberg, Cell 2022, 185, 2853–2878.
- 32Y. Xiang, Q. Chen, Y. Nan, M. Liu, Z. Xiao, Y. Yang, J. Zhang, X. Ying, X. Long, S. Wang, J. Sun, Q. Huang, K. Ai, Adv. Funct. Mater. 2024, 34, 2312092.
- 33S. M. Andrabi, N. S. Sharma, A. Karan, S. M. S. Shahriar, B. Cordon, B. Ma, J. Xie, Adv. Sci. 2023, 10, 2303259.
- 34J. Yu, J. Xu, S. Ma, C. Wang, Q. Miao, L. Wang, G. Chen, Chem. Biomed. Imaging 2024, 2, 401–412.
- 35H. Alimoradi, K. Greish, A. B. Gamble, G. I. Giles, Pharma. Nanotechnol. 2019, 7, 279–303.
- 36Z. Wang, A. Jin, Z. Yang, W. Huang, ACS Nano 2023, 17, 8935–8965.
- 37Y. Yang, Z. Huang, L.-L. Li, Nanoscale 2021, 13, 444–459.
- 38M. Qi, X. Ren, W. Li, Y. Sun, X. Sun, C. Li, S. Yu, L. Xu, Y. Zhou, S. Song, B. Dong, L. Wang, Nano Today 2022, 43, 101447.
- 39D. Li, X. Chen, W. Dai, Q. Jin, D. Wang, J. Ji, B. Z. Tang, Adv. Mater. 2024, 36, 2306476.
- 40X. Zhang, J. Guo, Z. Zhou, K. Feng, H. Liu, Y. Ruan, R. Chen, Z. Liu, T. Zhang, L. Tang, X. Sun, Chem. Biomed. Imaging 2024, 2, 275–282.
- 41X. Bao, S. Zheng, L. Zhang, A. Shen, G. Zhang, S. Liu, J. Hu, Angew. Chem. Int. Ed. 2022, 61, e202207250.
- 42B. Chen, Y. Sun, H. Sun, N. Cong, R. Ma, X. Qian, J. Lyu, X. Fu, F. Chi, H. Li, Y. Liu, D. Ren, W. Bu, ACS Nano 2024, 18, 33232–33244.
- 43D. Li, S. Cai, P. Wang, H. Cheng, B. Cheng, Y. Zhang, G. Liu, Adv. Healthcare Mater. 2023, 12, 2300263.
- 44P. H. Zhao, Y. L. Wu, X. Y. Li, L. L. Feng, L. Zhang, B. Y. Zheng, M. R. Ke, J. D. Huang, Angew. Chem. Int. Ed. 2021, 60, 1–77.
- 45M. Miretti, T. C. Tempesti, C. G. Prucca, M. T. Baumgartner, Bioorgan. Med. Chem. 2020, 28, 115355.
- 46H. C. Wilbur, J. N. Durham, S. J. Lim, K. Purtell, K. M. Bever, D. A. Laheru, A. De Jesus-Acosta, N. S. Azad, B. Wilt, L. A. Diaz, D. T. Le, H. Wang, Cancer Res. Commun. 2023, 3, 1672–1677.
- 47X. Liu, A. Situ, Y. Kang, K. R. Villabroza, Y. Liao, C. H. Chang, T. Donahue, A. E. Nel, H. Meng, ACS Nano 2016, 10, 2702–2715.
- 48X. Liu, J. Jiang, Y. P. Liao, I. Tang, E. Zheng, W. Qiu, M. Lin, X. Wang, Y. Ji, K. C. Mei, Q. Liu, C. H. Chang, Z. A. Wainberg, A. E. Nel, H. Meng, Adv. Sci. 2021, 8, 2002147.
- 49H. Chen, T. Shi, Y. Wang, Z. Liu, F. Liu, H. Zhang, X. Wang, Z. Miao, B. Liu, M. Wan, C. Mao, J. Wei, J. Am. Chem. Soc. 2021, 143, 12025–12037.
- 50Y.-C. Sung, P.-R. Jin, L.-A. Chu, F.-F. Hsu, M.-R. Wang, C.-C. Chang, S.-J. Chiou, J. T. Qiu, D.-Y. Gao, C.-C. Lin, Y.-S. Chen, Y.-C. Hsu, J. Wang, F.-N. Wang, P.-L. Yu, A.-S. Chiang, A. Y.-T. Wu, J. J.-S. Ko, C. P.-K. Lai, T.-T. Lu, Y. Chen, Nat. Nanotechnol. 2019, 14, 1160–1169.
- 51C. Yang, G. Mu, Y. Zhang, Y. Gao, W. Zhang, J. Liu, W. Zhang, P. Li, L. Yang, Z. Yang, J. Gao, J. Liu, Adv. Mater. 2022, 34, 2202625.
- 52X. Chen, F. Jia, Y. Li, Y. Deng, Y. Huang, W. Liu, Q. Jin, J. Ji, Biomaterials 2020, 246, 119999.
- 53J. Fang, W.l Islam, H. Maeda, S. Wilhelm, Adv. Drug. Deli. Rev. 2020, 157, 142–160.
- 54H. Chen, T. Li, Z. Liu, S. Tang, J. Tong, Y. Tao, Z. Zhao, N. Li, C. Mao, J. Shen, M. Wan, Nat. Commun. 2023, 14, 941.
- 55D. Cheng, J. Peng, Y. Lv, D. Su, D. Liu, M. Chen, L. Yuan, X. Zhang, J. Am. Chem. Soc. 2019, 141, 6352–6361.
- 56X. Dong, H.-J. Liu, H.-Y. Feng, S.-C. Yang, X.-L. Liu, X. Lai, Q. Lu, J. F. Lovell, H.-Z. Chen, C. Fang, Nano Lett. 2019, 19, 997–1008.
- 57Y. Mantri, B. Davidi, J. E. Lemaster, A. Hariri, J. V. Jokerst, Nanoscale 2020, 12, 10511–10520.
- 58P. Liu, Y. Wang, Y. Liu, F. Tan, J. Li, N. Li, Theranostics 2020, 10, 6774–6789.
- 59D. B. Doroshow, S. Bhalla, M. B. Beasley, L. M. Sholl, K. M. Kerr, S. Gnjatic, I. I. Wistuba, D. L. Rimm, M. S. Tsao, F. R. Hirsch, Nat. Rev. Clin. Oncol. 2021, 18, 345–362.
- 60P. Sharma, J. P. Allison, Science 2015, 348, 56–61.
- 61J. Zhang, Y. Hu, X. Wen, Z. Yang, Z. Wang, Z. Feng, H. Bai, Q. Xue, Y. Miao, T. Tian, P. Zheng, J. Zhang, J. Li, L. Qiu, J.-J. Xu, D. Ye, Nat. Nanotechnol. 2025, 20, 563–574.
This is the
German version
of Angewandte Chemie.
Note for articles published since 1962:
Do not cite this version alone.
Take me to the International Edition version with citable page numbers, DOI, and citation export.
We apologize for the inconvenience.
