Efficacy evaluation of extracellular vesicle drug delivery system in orthotopic intravesical perfusion for bladder cancer_Journal of Biomedical Engineering

Authors：

ZHENG Mei ¹ , GAO Xin ¹ , LIU Juan ² , TAN Lulu ³ ,  SONG Yawei ¹

1. Laboratory Animal Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China;
2. Guangdong Wens Dahuanong Biotechnology Co., Ltd., Yunfu, Guangdong 527400, P. R. China;
3. Guangdong GemPharmatech Co., Ltd., Foshan, Guangdong 528255, P. R. China;

Corresponding?author：

SONG Yawei, Email: 17827062427@163.com

Keywords：

Bladder cancer; Extracellular vesicles; Pirarubicin; Intravesical perfusion

DOI：

10.7507/1001-5515.202605010

Video：

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To address the clinical challenges of limited therapeutic efficacy and pronounced toxicity associated with conventional intravesical chemotherapy due to the bladder mucosal barrier, this study constructs an extracellular vesicles (EVs)-based drug delivery system loaded with pirarubicin (THP), designated as EVs@THP. EVs derived from MB49 bladder tumor cells were extracted by ultracentrifugation and loaded with THP. Structural characterization confirmed that EVs@THP maintained stable vesicle structure. In vitro cell experiments showed that EVs@THP could be efficiently internalized by bladder cancer cells and presented stronger tumor killing ability compared with free THP. In vivo experiments using orthotopic bladder cancer mouse models further proved that EVs@THP possessed better tissue penetration and intravesical retention after perfusion, with significantly superior antitumor efficacy to free THP. MB49 cell-derived EVs are promising delivery carriers for THP. The EVs@THP system with good biocompatibility and targeting ability can effectively improve the outcome of bladder cancer intravesical chemotherapy, providing experimental evidence for the development and transformation of novel intravesical therapeutic regimens.

Citation： ZHENG Mei, GAO Xin, LIU Juan, TAN Lulu, SONG Yawei. Efficacy evaluation of extracellular vesicle drug delivery system in orthotopic intravesical perfusion for bladder cancer. Journal of Biomedical Engineering, 2026, 43(5): 1068-1074. doi: 10.7507/1001-5515.202605010 Copy

1.	Halaseh S A, Halaseh S, Alali Y, et al. A review of the etiology and epidemiology of bladder cancer: all you need to know[J]. Cureus, 2022, 14(7): e27330.
2.	Flaig T W, Spiess P E, Abern M, et al. Bladder cancer, version 3.2024 featured updates to the NCCN guidelines[J]. J Natl Compr Canc Netw, 2024, 22(4): 216-225.
3.	李輝章, 鄭榮壽, 杜靈彬, 等. 中國膀胱癌流行現狀與趨勢分析[J]. 中華腫瘤雜志, 2021, 43(3): 293-298.
4.	Monda S, Pratsinis M, Lui H S, et al. Secondary bladder cancer after prostate cancer treatment: an age-matched comparison between radiation and surgery[J]. Eur Urol Focus, 2024, 10(3): 448-453.
5.	Zhang S Y, Lin T H, Xiong X Y, et al. Targeting histone modifiers in bladder cancer therapy - preclinical and clinical evidence[J]. Nat Rev Urol, 2024, 21(8): 495-511.
6.	Tong T, Guan Y, Gao Y, et al. Smart nanocarriers as therapeutic platforms for bladder cancer[J]. Nano Res, 2021, 15(3): 2157-2176.
7.	李林峰, 高漓. 納米載藥系統在泌尿系腫瘤治療中應用的研究進展[J]. 現代藥物與臨床, 2020, 35(8): 1724-1728.
8.	Guo H, Xu W, Chen J, et al. Positively charged polypeptide nanogel enhances mucoadhesion and penetrability of 10-hydroxycamptothecin in orthotopic bladder carcinoma[J]. J Control Release, 2017, 259: 136-148.
9.	Zhang Q, Neoh K G, Xu L Q, et al. Functionalized mesoporous silica nanoparticles with mucoadhesive and sustained drug release properties for potential bladder cancer therapy[J]. Langmuir, 2014, 30(21): 6151-6161.
10.	Winnicka A, Brzeszczyńska J, Saluk J, et al. Nanomedicine in bladder cancer therapy[J]. Int J Mol Sci, 2024, 25(19): 10388.
11.	王琎, 陳建英. 細胞外囊泡研究新進展[J]. 中國組織工程研究, 2017, 21(4): 621-626.
12.	孟婉蓉, 李靈, 朱桂全. 外泌體作為藥物傳遞系統的前景及挑戰[J]. 生物醫學工程學雜志, 2020, 37(4): 714-720.
13.	Li G, Wu S, Liu J, et al. Narrow bandgap Schottky heterojunction sonosensitizer with high electron-hole separation boosted sonodynamic therapy in bladder cancer[J]. Adv Mater, 2024, 36(26): e2401252.
14.	Xu G L, Jin J, Fu Z H, et al. Extracellular vesicle-based drug overview: research landscape, quality control and nonclinical evaluation strategies[J]. Signal Transduct Target Ther, 2025, 10(1): 255.
15.	Espiau-Romera P, Gordo-Ortiz A, Ortiz-de-Solórzano I, et al. Metabolic features of tumor-derived extracellular vesicles: challenges and opportunities[J]. Extracell Vesicles Circ Nucl Acids, 2024, 5(3): 455-470.
16.	Xu Y X, Feng K H, Zhao H C, et al. Tumor-derived extracellular vesicles as messengers of natural products in cancer treatment[J]. Theranostics, 2022, 12(4): 1683-1714.
17.	Wang J, Yin B, Lian J, et al. Extracellular vesicles as drug delivery system for cancer therapy[J]. Pharmaceutics, 2024, 16(8): 1029.
18.	Zhang P, Wu G, Zhang D, et al. Mechanisms and strategies to enhance penetration during intravesical drug therapy for bladder cancer[J]. J Control Release, 2023, 354: 69-79.
19.	Górski J, Gajewski W, Ziembicki H, et al. Nanoparticles as drug delivery systems in intravesical therapy for non-muscle invasive bladder cancer: a narrative review[J]. Cureus, 2025, 17(8): e91103.
20.	孫波, 呂宗強, 羅寧, 等. Angiopep-2修飾的細菌外囊泡載藥系統治療膠質母細胞瘤效果研究[J]. 藥學實踐與服務, 2025, 43(10): 481-490.
21.	Kumbham S, Rahman K M M, Foster B A, et al. A comprehensive review of current approaches in bladder cancer treatment[J]. ACS Pharmacol Transl Sci, 2025, 8(2): 286-307.
22.	Jain P, Kathuria H, Momin M. Clinical therapies and nano drug delivery systems for urinary bladder cancer[J]. Pharmacol Ther, 2021, 226: 107871.
23.	van Hoogstraten L M C, Vrieling A, van der Heijden A G, et al. Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice[J]. Nat Rev Clin Oncol, 2023, 20(5): 287-304.
24.	Liu J, Yang T Y, Dai L Q, et al. Intravesical chemotherapy synergize with an immune adjuvant by a thermo-sensitive hydrogel system for bladder cancer[J]. Bioact Mater, 2024, 31: 315-332.
25.	Ascione C M, Napolitano F, Esposito D, et al. Role of FGFR3 in bladder cancer: treatment landscape and future challenges[J]. Cancer Treat Rev, 2023, 115: 102530.
26.	Zheng B, Liu Z, Wang H, et al. R11 modified tumor cell membrane nanovesicle-camouflaged nanoparticles with enhanced targeting and mucus-penetrating efficiency for intravesical chemotherapy for bladder cancer[J]. J Control Release, 2022, 351: 834-846.
27.	Zheng B, Zhang H, Wang J, et al. A mucoadhesive-to-penetrating nanomotors-in-hydrogel system for urothelium-oriented intravesical drug delivery[J]. J Nanobiotechnology, 2024, 22(1): 560.
28.	Bhandari P, Novikova G, Goergen C J, et al. Ultrasound beam steering of oxygen nanobubbles for enhanced bladder cancer therapy[J]. Sci Rep, 2018, 8(1): 3112.
29.	Guo H, Li F, Qiu H, et al. Synergistically enhanced mucoadhesive and penetrable polypeptide nanogel for efficient drug delivery to orthotopic bladder cancer[J]. Research, 2020, 2020: 8970135.
30.	邊素艷, 劉宏斌. 細胞外囊泡的分離及鑒定方法[J]. 新醫學, 2019, 50(9): 658-662.
31.	Zhao Z, Wijerathne H, Godwin A K, et al. Isolation and analysis methods of extracellular vesicles (EVs)[J]. Extracell Vesicles Circ Nucl Acids, 2021, 2(1): 80-103.
32.	Huang Z X, Lu C Q, Wang Y X, et al. Enhancing anti-tumor effects of engineered extracellular vesicles via endocytosis route switching and interferon response suppression[J]. Adv Sci (Weinh), 2025, 12(46): e15472.
33.	Zhou X, Miao Y Q, Wang Y, et al. Tumour-derived extracellular vesicle membrane hybrid lipid nanovesicles enhance siRNA delivery by tumour-homing and intracellular freeway transportation[J]. J Extracell Vesicles, 2022, 11(3): e12198.
34.	Mohammadipoor A, Hershfield M R, Linsenbardt H R, et al. Biological function of extracellular vesicles (EVs): a review of the field[J]. Mol Biol Rep, 2023, 50(10): 8639-8651.
35.	Zhang N, Li D, Shao J, et al. Animal models for bladder cancer: the model establishment and evaluation[J]. Oncol Lett, 2015, 9(4): 1515-1519.
36.	Qiu X, Cao K, Lin T, et al. Drug delivery system based on dendritic nanoparticles for enhancement of intravesical instillation[J]. Int J Nanomedicine, 2017, 12: 7365-7374.
37.	Liu Z, Joshi R, Zhou Z, et al. Intravesical pressure-driven piezoelectric nanoneedles with optimized morphology for enhanced bladder cancer therapy via tunneling nanotubes-mediated intercellular delivery[J]. Nano Energy, 2026, 149: 111716.

1. Halaseh S A, Halaseh S, Alali Y, et al. A review of the etiology and epidemiology of bladder cancer: all you need to know[J]. Cureus, 2022, 14(7): e27330.
2. Flaig T W, Spiess P E, Abern M, et al. Bladder cancer, version 3.2024 featured updates to the NCCN guidelines[J]. J Natl Compr Canc Netw, 2024, 22(4): 216-225.
3. 李輝章, 鄭榮壽, 杜靈彬, 等. 中國膀胱癌流行現狀與趨勢分析[J]. 中華腫瘤雜志, 2021, 43(3): 293-298.
4. Monda S, Pratsinis M, Lui H S, et al. Secondary bladder cancer after prostate cancer treatment: an age-matched comparison between radiation and surgery[J]. Eur Urol Focus, 2024, 10(3): 448-453.
5. Zhang S Y, Lin T H, Xiong X Y, et al. Targeting histone modifiers in bladder cancer therapy - preclinical and clinical evidence[J]. Nat Rev Urol, 2024, 21(8): 495-511.
6. Tong T, Guan Y, Gao Y, et al. Smart nanocarriers as therapeutic platforms for bladder cancer[J]. Nano Res, 2021, 15(3): 2157-2176.
7. 李林峰, 高漓. 納米載藥系統在泌尿系腫瘤治療中應用的研究進展[J]. 現代藥物與臨床, 2020, 35(8): 1724-1728.
8. Guo H, Xu W, Chen J, et al. Positively charged polypeptide nanogel enhances mucoadhesion and penetrability of 10-hydroxycamptothecin in orthotopic bladder carcinoma[J]. J Control Release, 2017, 259: 136-148.
9. Zhang Q, Neoh K G, Xu L Q, et al. Functionalized mesoporous silica nanoparticles with mucoadhesive and sustained drug release properties for potential bladder cancer therapy[J]. Langmuir, 2014, 30(21): 6151-6161.
10. Winnicka A, Brzeszczyńska J, Saluk J, et al. Nanomedicine in bladder cancer therapy[J]. Int J Mol Sci, 2024, 25(19): 10388.
11. 王琎, 陳建英. 細胞外囊泡研究新進展[J]. 中國組織工程研究, 2017, 21(4): 621-626.
12. 孟婉蓉, 李靈, 朱桂全. 外泌體作為藥物傳遞系統的前景及挑戰[J]. 生物醫學工程學雜志, 2020, 37(4): 714-720.
13. Li G, Wu S, Liu J, et al. Narrow bandgap Schottky heterojunction sonosensitizer with high electron-hole separation boosted sonodynamic therapy in bladder cancer[J]. Adv Mater, 2024, 36(26): e2401252.
14. Xu G L, Jin J, Fu Z H, et al. Extracellular vesicle-based drug overview: research landscape, quality control and nonclinical evaluation strategies[J]. Signal Transduct Target Ther, 2025, 10(1): 255.
15. Espiau-Romera P, Gordo-Ortiz A, Ortiz-de-Solórzano I, et al. Metabolic features of tumor-derived extracellular vesicles: challenges and opportunities[J]. Extracell Vesicles Circ Nucl Acids, 2024, 5(3): 455-470.
16. Xu Y X, Feng K H, Zhao H C, et al. Tumor-derived extracellular vesicles as messengers of natural products in cancer treatment[J]. Theranostics, 2022, 12(4): 1683-1714.
17. Wang J, Yin B, Lian J, et al. Extracellular vesicles as drug delivery system for cancer therapy[J]. Pharmaceutics, 2024, 16(8): 1029.
18. Zhang P, Wu G, Zhang D, et al. Mechanisms and strategies to enhance penetration during intravesical drug therapy for bladder cancer[J]. J Control Release, 2023, 354: 69-79.
19. Górski J, Gajewski W, Ziembicki H, et al. Nanoparticles as drug delivery systems in intravesical therapy for non-muscle invasive bladder cancer: a narrative review[J]. Cureus, 2025, 17(8): e91103.
20. 孫波, 呂宗強, 羅寧, 等. Angiopep-2修飾的細菌外囊泡載藥系統治療膠質母細胞瘤效果研究[J]. 藥學實踐與服務, 2025, 43(10): 481-490.
21. Kumbham S, Rahman K M M, Foster B A, et al. A comprehensive review of current approaches in bladder cancer treatment[J]. ACS Pharmacol Transl Sci, 2025, 8(2): 286-307.
22. Jain P, Kathuria H, Momin M. Clinical therapies and nano drug delivery systems for urinary bladder cancer[J]. Pharmacol Ther, 2021, 226: 107871.
23. van Hoogstraten L M C, Vrieling A, van der Heijden A G, et al. Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice[J]. Nat Rev Clin Oncol, 2023, 20(5): 287-304.
24. Liu J, Yang T Y, Dai L Q, et al. Intravesical chemotherapy synergize with an immune adjuvant by a thermo-sensitive hydrogel system for bladder cancer[J]. Bioact Mater, 2024, 31: 315-332.
25. Ascione C M, Napolitano F, Esposito D, et al. Role of FGFR3 in bladder cancer: treatment landscape and future challenges[J]. Cancer Treat Rev, 2023, 115: 102530.
26. Zheng B, Liu Z, Wang H, et al. R11 modified tumor cell membrane nanovesicle-camouflaged nanoparticles with enhanced targeting and mucus-penetrating efficiency for intravesical chemotherapy for bladder cancer[J]. J Control Release, 2022, 351: 834-846.
27. Zheng B, Zhang H, Wang J, et al. A mucoadhesive-to-penetrating nanomotors-in-hydrogel system for urothelium-oriented intravesical drug delivery[J]. J Nanobiotechnology, 2024, 22(1): 560.
28. Bhandari P, Novikova G, Goergen C J, et al. Ultrasound beam steering of oxygen nanobubbles for enhanced bladder cancer therapy[J]. Sci Rep, 2018, 8(1): 3112.
29. Guo H, Li F, Qiu H, et al. Synergistically enhanced mucoadhesive and penetrable polypeptide nanogel for efficient drug delivery to orthotopic bladder cancer[J]. Research, 2020, 2020: 8970135.
30. 邊素艷, 劉宏斌. 細胞外囊泡的分離及鑒定方法[J]. 新醫學, 2019, 50(9): 658-662.
31. Zhao Z, Wijerathne H, Godwin A K, et al. Isolation and analysis methods of extracellular vesicles (EVs)[J]. Extracell Vesicles Circ Nucl Acids, 2021, 2(1): 80-103.
32. Huang Z X, Lu C Q, Wang Y X, et al. Enhancing anti-tumor effects of engineered extracellular vesicles via endocytosis route switching and interferon response suppression[J]. Adv Sci (Weinh), 2025, 12(46): e15472.
33. Zhou X, Miao Y Q, Wang Y, et al. Tumour-derived extracellular vesicle membrane hybrid lipid nanovesicles enhance siRNA delivery by tumour-homing and intracellular freeway transportation[J]. J Extracell Vesicles, 2022, 11(3): e12198.
34. Mohammadipoor A, Hershfield M R, Linsenbardt H R, et al. Biological function of extracellular vesicles (EVs): a review of the field[J]. Mol Biol Rep, 2023, 50(10): 8639-8651.
35. Zhang N, Li D, Shao J, et al. Animal models for bladder cancer: the model establishment and evaluation[J]. Oncol Lett, 2015, 9(4): 1515-1519.
36. Qiu X, Cao K, Lin T, et al. Drug delivery system based on dendritic nanoparticles for enhancement of intravesical instillation[J]. Int J Nanomedicine, 2017, 12: 7365-7374.
37. Liu Z, Joshi R, Zhou Z, et al. Intravesical pressure-driven piezoelectric nanoneedles with optimized morphology for enhanced bladder cancer therapy via tunneling nanotubes-mediated intercellular delivery[J]. Nano Energy, 2026, 149: 111716.

Journal of Biomedical Engineering

Efficacy evaluation of extracellular vesicle drug delivery system in orthotopic intravesical perfusion for bladder cancer

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