Citation: Bin Wan, Qiu Wang, Xiwei Jiang, Xianlu Zhang, Xiaoyuan Fan, Fengxiang Liu, Shipeng Ning, Meiling Zhang, Dongyan Liang, Lianwen Qi, Zhonggui He, Yinglei Zhai, Kaiyuan Wang, Jin Sun, Wei Tang. Augmenting macropinocytosis enhances the apoptotic body-mediated tumor deep penetration of nanomedicines[J]. Chinese Chemical Letters, ;2026, 37(8): 112285. doi: 10.1016/j.cclet.2025.112285 shu

Augmenting macropinocytosis enhances the apoptotic body-mediated tumor deep penetration of nanomedicines

Bin Wan ^{a, b, 1} ,
Qiu Wang ^{c, 1} ,
Xiwei Jiang ^{d, 1} ,
Xianlu Zhang ^{e, 1} ,
Xiaoyuan Fan ^b ,
Fengxiang Liu ^b ,
Shipeng Ning ^a ,
Meiling Zhang ^a ,
Dongyan Liang ^a ,
Lianwen Qi ^f ,
Zhonggui He ^{b, g} ,
Yinglei Zhai ^b ,
Kaiyuan Wang ^{b, g, h, *,} ,
Jin Sun ^{b, g, *,} ,
Wei Tang ^{a, *,}

a.
Department of Breast Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, China
b.
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
c.
Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China
d.
School of Medical Devices, Shenyang Pharmaceutical University, Shenyang 110016, China
e.
Department of Urology, the First Hospital of China Medical University, Shenyang 110000, China
f.
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
g.
Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang 110016, China
h.
Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore

wangkaiyuan@hotmail.com

sunjin@syphu.edu.cn

tang_wei_gxmuch@163.com

Received Date: 14 August 2025
Revised Date: 12 December 2025
Accepted Date: 15 December 2025
Available Online: 15 December 2025

Figures(6)

Overcoming the penetration barrier of nanomedicines remains a paramount challenge in antitumor therapy. Apoptotic bodies (ApoBDs), which are naturally generated from apoptotic cells, can mediate a potent neighboring effect by transferring drug to neighboring tumor cells via macropinocytosis. To amplify this process, we developed a tumor microenvironment-responsive nanoplatform (named as AD-NVs@CPP) to selectively enhance chemokine (C-X-C motif) receptor 4 (CXCR4) receptor-stimulated macropinocytosis. This platform was constructed by co-encapsulating doxorubicin (DOX) and the hypoxia-activated prodrug AQ4N into homologous tumor cell membrane-derived nanovesicles (AD-NVs), followed by biomineralization of a calcium phosphate (CaP) shell that incorporated a CXCR4-targeting peptide (RFFE-SHAPAKPVSLSYR). The resultant AD-NVs@CPP exhibited a core-shell structure with a hydrodynamic diameter of ~180 nm and achieved a high peptide encapsulation efficiency of 81.6% ± 8.2%. The CaP shell demonstrated excellent pH-responsive dissolution, releasing ~50% of the peptide within 24 h at pH 6.5 (vs. negligible release at pH 7.4), which consequently promoted cellular uptake and enhanced cytotoxicity under acidic conditions in vitro. Additionally, AD-NVs@CPP-induced ApoBDs served as efficient drug reservoirs, delivering drugs to adjacent cells with an IC₅₀ value of 0.98 µg/mL (in terms of protein concentration). In vivo, AD-NVs@CPP significantly prolonged the blood circulation time (increasing the half-life of DOX compared to the free drug solution) and improved tumor accumulation. Crucially, it enabled programmed drug penetration: AQ4N was selectively delivered into deep hypoxic tumor regions, mediating comprehensive tumor growth inhibition while maintaining a favorable safety profile. This work provides a robust strategy for achieving deep tumor penetration through the synergistic enhancement of macropinocytosis and the ApoBD-mediated neighboring effect.
- Cytomembrane nanovesicles,
- Apoptotic body,
- Macropinocytosis,
- Neighboring effect,
- Programmed drug penetration
1. [1]
  C. Wang, S. Chen, Y. Wang, et al., Adv. Mater. 30 (2018) 1706407. doi: 10.1002/adma.201706407
2. [2]
  S. Guo, Y. Wang, L. Miao, et al., ACS Nano 7 (2013) 9896–9904. doi: 10.1021/nn403606m
3. [3]
  J. Jiang, X. Cui, Y. Huang, et al., Nano Biomed. Eng. 16 (2024) 152–187. doi: 10.26599/nbe.2024.9290060
4. [4]
  C. Ju, R. Mo, J. Xue, et al., Angew. Chem. 126 (2014) 6367–6372. doi: 10.1002/ange.201311227
5. [5]
  D. Zhao, W. Tao, S. Li, et al., Sci. Adv. 7 (2021) eabg0880. doi: 10.1126/sciadv.abg0880
6. [6]
  C.D. Gregory, M.P. Rimmer, J. Pathol. 260 (2023) 592–608. doi: 10.1002/path.6138
7. [7]
  X. Shen, D. Pan, Q. Gong, et al., Bioact. Mater. 32 (2023) 445–472. doi: 10.3934/era.2024022
8. [8]
  W. Palm, Philos. Trans. R. Soc. B: Biol. Sci. 374 (2019) 20180285. doi: 10.1098/rstb.2018.0285
9. [9]
  A.S. Desai, M.R. Hunter, A.N. Kapustin, Philos. Trans. R. Soc. B: Biol. Sci. 374 (2019) 20180156. doi: 10.1098/rstb.2018.0156
10. [10]
  A.M. Fulton, Chemokine receptors in cancer, in: B. Furusato, J.S. Rhim (Eds.), Introduction to the CXCR4 and Cancer, Humana Press, Inc., New Jersey, 2009, pp. 31–45.
11. [11]
  Z. Wang, Y. Ma, X. Yu, et al. Adv. Funct. Mater. 28 (2018) 1800732. doi: 10.1002/adfm.201800732
12. [12]
  H. Guo, Y. Ge, X. Li, et al. Signal Transduc. Target. Ther. 2 (2017): 17033. doi: 10.1038/sigtrans.2017.33
13. [13]
  C. Yang, F. Zhang, F. Chen, et al., Adv. Healthc. Mater. 12 (2023) 2202064. doi: 10.1002/adhm.202202064
14. [14]
  L. Sun, X. Luo, C. Zhou, et al. Chin. Chem. Lett. 35 (2024) 108803. doi: 10.1016/j.cclet.2023.108803
15. [15]
  E.B. Cepeda, T. Dediulia, J. Fernando, et al., Biochim. Biophys. Acta 1853 (2015) 1205–1218. doi: 10.1016/j.bbamcr.2015.02.012
16. [16]
  G. Jiang, H. Chen, J. Huang, et al., Adv. Sci. 7 (2020) 1903290. doi: 10.1002/advs.201903290
17. [17]
  T.R.M. Filippo, L.T. Galindo, G.F. Barnabe, et al., Stem Cell Res. 41 (2020) 101631.
18. [18]
  K. Wang, X. Zhang, H. Ye, et al., Nat. Commun. 14 (2023) 6748. doi: 10.1038/s41467-023-42155-z
19. [19]
  L. Ribovski, B. Joshi, J. Gao, et al., Extr. Vesicles Circ. Nucleic Acids 4 (2023) 283–305. doi: 10.20517/evcna.2023.26
20. [20]
  G. Tanaka, I. Nakase, Y. Fukuda, et al., Chem. Biol. 19 (2012) 1437–1446. doi: 10.1016/j.chembiol.2012.09.011
21. [21]
  A. Sharma, J.F. Arambula, S. Koo, et al., Chem. Soc. Rev. 48 (2019) 771–813. doi: 10.1039/c8cs00304a
22. [22]
  Y. Li, L. Zhao, X.F. Li, Front. Oncol. 11 (2021) 700407. doi: 10.3389/fonc.2021.700407
23. [23]
  U.M. Kumar, U. Kumar, A.K. Singh, Nano Biomed. Eng. 14 (2022) 38–52.
24. [24]
  Y. Wang, S. Luo, Y. Wu, et al., ACS Nano 14 (2020) 17046–17062. doi: 10.1021/acsnano.0c06415
25. [25]
  S. Luo, C. Liang, Q. Zhang, et al. Chin. Chem. Lett. 34 (2023) 107666. doi: 10.1016/j.cclet.2022.07.009
26. [26]
  D. Gupta, O.P.B. Wiklander, M.J.A. Wood, et al., Extr. Vesicles Circ. Nucleic Acids 4 (2023) 170–190. doi: 10.20517/evcna.2023.12
27. [27]
  Y. He, K. Wang, Y. Lu, et al., Nano Lett. 22 (2022) 1415–1424. doi: 10.1021/acs.nanolett.1c04962
28. [28]
  F. Sun, S. Ning, X. Fan, et al., Nano Today 61 (2025) 102604. doi: 10.1016/j.nantod.2024.102604
29. [29]
  X. Wang, I.M. Lei, B. Li, et al. Chin. Chem. Lett. 37 (2026) 110990. doi: 10.1016/j.cclet.2025.110990
30. [30]
  S. Hu, R. Hao, Z. Yu, et al. Chin. Chem. Lett. 35 (2024) 108534. doi: 10.1016/j.cclet.2023.108534
31. [31]
  X. Wang, S. Ning, W. Tao, et al., Nano Today 56 (2024) 102311. doi: 10.1016/j.nantod.2024.102311
32. [32]
  G. Huang, W. Zheng, Y. Zhou, et al., Acta Pharm. Sin. B 14 (2024) 3855–3875. doi: 10.1016/j.apsb.2024.06.010
33. [33]
  S. Sheng, X. Yu, G. Xing, et al., Adv. Funct. Mater. 33 (2023) 2212118. doi: 10.1002/adfm.202212118
34. [34]
  Y. Yu, T. Li, M. Ou, et al., J. Control. Release 365 (2024) 469–479. doi: 10.1016/j.jconrel.2023.11.051
35. [35]
  J. Zhang, J. Guo, L. Wang, et al., J. Control. Release 376 (2024) 369–381.
36. [36]
  X. Wang, W. Chen, W. Zeng, et al., Acta Pharm. Sin. B 15 (2025) 3460–3486. doi: 10.1016/j.apsb.2025.04.033
37. [37]
  M. Sun, J. Yang, Y. Fan, et al., Adv. Sci. 10 (2023) 2303617. doi: 10.1002/advs.202303617
38. [38]
  R.J.C. Bose, N. Tharmalingam, F.J. Garcia Marques, et al., ACS Nano 14 (2020) 5818–5835. doi: 10.1021/acsnano.0c00921
39. [39]
  C. Carvalho, R.X. Santos, S. Cardoso, et al., Curr. Med. Chem. 16 (2009) 3267–3285. doi: 10.2174/092986709788803312
40. [40]
  V. Sokolova, M. Epple, Chemistry 27 (2021) 7471–7488. doi: 10.1002/chem.202005257
41. [41]
  S. Qing, C. Lyu, L. Zhu, et al., Adv. Mater. 32 (2020) 2002085. doi: 10.1002/adma.202002085
42. [42]
  R. Khalifehzadeh, H. Arami, Adv. Colloid Interface Sci. 279 (2020) 102157. doi: 10.1016/j.cis.2020.102157
43. [43]
  A. Pugazhendhi, T.N.J.I. Edison, B.K. Velmurugan, et al., Life Sci. 200 (2018) 26–30. doi: 10.1016/j.lfs.2018.03.023
44. [44]
  A. Varela-López, M. Battino, M.D. Navarro-Hortal, et al., Food Chem. Toxicol. 134 (2019) 110834. doi: 10.1016/j.fct.2019.110834
45. [45]
  G. Toffoli, M. Hadla, G. Corona, et al., Nanomedicine 10 (2015) 2963–2971. doi: 10.2217/nnm.15.118
1. [1]
  Junchen Peng , Xue Yin , Dandan Dong , Zhongyuan Guo , Qinqin Wang , Minmin Liu , Fei He , Bin Dai , Chaofeng Huang . Promotion effect of epoxy group neighboring single-atom Cu site on acetylene hydrochlorination. Chinese Chemical Letters, 2024, 35(6): 109508-. doi: 10.1016/j.cclet.2024.109508
2. [2]
  Yi Cao , Xiaojiao Ge , Yuanyuan Wei , Lulu He , Aiguo Wu , Juan Li . Tumor microenvironment-activatable neuropeptide-drug conjugates enhanced tumor penetration and inhibition via multiple delivery pathways and calcium deposition. Chinese Chemical Letters, 2024, 35(4): 108672-. doi: 10.1016/j.cclet.2023.108672
3. [3]
  Chen Liu , Tianqi Zhao , Jialing Zhou , Xiaoyun Hu , Dinghao Pan , Jinlong Li , Wei Li , Zhihui Dai . Optical lateral flow immune assay technology for body fluid sensing. Chinese Chemical Letters, 2026, 37(1): 110967-. doi: 10.1016/j.cclet.2025.110967
4. [4]
  Tong Tong , Lezong Chen , Siying Wu , Zhong Cao , Yuanbin Song , Jun Wu . Establishment of a leucine-based poly(ester amide)s library with self-anticancer effect as nano-drug carrier for colorectal cancer treatment. Chinese Chemical Letters, 2024, 35(12): 109689-. doi: 10.1016/j.cclet.2024.109689
5. [5]
  Chang Liu , Tao Wu , Lijiao Deng , Xuzi Li , Xin Fu , Shuzhen Liao , Wenjie Ma , Guoqiang Zou , Hai Yang . Programmed DNA walkers for biosensors. Chinese Chemical Letters, 2024, 35(9): 109307-. doi: 10.1016/j.cclet.2023.109307
6. [6]
  Wenhao Wang , Siyuan Peng , Zhengwei Huang , Xin Pan . Tuning amino/hydroxyl ratios of nanovesicles to manipulate protein corona-mediated in vivo fate. Chinese Chemical Letters, 2024, 35(11): 110134-. doi: 10.1016/j.cclet.2024.110134
7. [7]
  Yunyan Li , Zimin Cai , Zhicheng Wang , Sifeng Zhu , Wendian Liu , Cheng Wang . Construction of biomimetic hybrid nanovesicles based on M1 macrophage-derived exosomes for therapy of cancer. Chinese Chemical Letters, 2025, 36(4): 109942-. doi: 10.1016/j.cclet.2024.109942
8. [8]
  Yangyang Zhang , Lu Qiu , Houying Li , Wenli Cai , Ergang Liu , Hongtao Zhang , Bahtiyor Muhitdinov , Jianming Liang , Yongzhuo Huang . Biomimetically engineered plant-derived exosomes-like nanovesicles for rheumatoid arthritis therapy. Chinese Chemical Letters, 2025, 36(9): 110658-. doi: 10.1016/j.cclet.2024.110658
9. [9]
  Youcheng Hu , Guichan Li , Chunli Qi , Xiaoyan Lin , Xingwang Zhang , Hao Wang . Macrophage membrane-engineered nanovesicles for targeted delivery of emodin in ulcerative colitis via chemotactic homing. Chinese Chemical Letters, 2026, 37(7): 111727-. doi: 10.1016/j.cclet.2025.111727
10. [10]
  Gaowa Xing , Yuting Shang , Xiaorui Wang , Zengnan Wu , Qiang Zhang , Jiebing Ai , Qiaosheng Pu , Ling Lin . A microfluidic biosensor for multiplex immunoassay of foodborne pathogens agitated by programmed audio signals. Chinese Chemical Letters, 2024, 35(10): 109491-. doi: 10.1016/j.cclet.2024.109491
11. [11]
  Yue Jin , Kun Dai , Lu Song , Xiaolei Zuo , Guangbao Yao , Min Li . Valence-programmed RNA origami for potent innate immune activation. Chinese Chemical Letters, 2025, 36(10): 110744-. doi: 10.1016/j.cclet.2024.110744
12. [12]
  Jiahao Liu , Peng Liu , Junhong Duan , Qiongxuan Xie , Jie Feng , Hongpei Tan , Ze Mi , Ying Li , Yunjie Liao , Pengfei Rong , Wenhu Zhou , Xiang Gao . Macrophages-mediated tumor accumulation and deep penetration of bismuth/manganese biomineralized nanoparticles for enhanced radiotherapy. Chinese Chemical Letters, 2024, 35(12): 109632-. doi: 10.1016/j.cclet.2024.109632
13. [13]
  Shushan Mo , Zhaoshuo Wang , Dandan Ding , Zhengzheng Yan , Yunlu Dai , Jinchao Zhang , Huifang Liu , Tianjiao Liang , Jianfei Tong , Zhenhua Li , Xueyi Wang . The synthesis and evaluation of novel BPA derivatives for enhanced blood-brain barrier penetration and boron neutron capture therapy. Chinese Chemical Letters, 2025, 36(5): 110190-. doi: 10.1016/j.cclet.2024.110190
14. [14]
  Le Chen , Hui Wang , Yiyun Cheng . An erucin-anchored polymer with excellent amyloidosis inhibition and direct cell membrane penetration ability for intracellular protein delivery. Chinese Chemical Letters, 2026, 37(4): 111172-. doi: 10.1016/j.cclet.2025.111172
15. [15]
  Fanxin Kong , Hongzhi Wang , Huimei Duan . Inhibition effect of sulfation on Pt/TiO2 catalysts in methane combustion. Chinese Journal of Structural Chemistry, 2024, 43(5): 100287-100287. doi: 10.1016/j.cjsc.2024.100287
16. [16]
  Min Fu , Pan He , Sen Zhou , Wenqiang Liu , Bo Ma , Shiying Shang , Yaohao Li , Ruihan Wang , Zhongping Tan . An unexpected stereochemical effect of thio-substituted Asp in native chemical ligation. Chinese Chemical Letters, 2024, 35(8): 109434-. doi: 10.1016/j.cclet.2023.109434
17. [17]
  Yixia Zhang , Caili Xue , Yunpeng Zhang , Qi Zhang , Kai Zhang , Yulin Liu , Zhaohui Shan , Wu Qiu , Gang Chen , Na Li , Hulin Zhang , Jiang Zhao , Da-Peng Yang . Cocktail effect of ionic patch driven by triboelectric nanogenerator for diabetic wound healing. Chinese Chemical Letters, 2024, 35(8): 109196-. doi: 10.1016/j.cclet.2023.109196
18. [18]
  Yuan Dong , Mutian Ma , Zhenyang Jiao , Sheng Han , Likun Xiong , Zhao Deng , Yang Peng . Effect of electrolyte cation-mediated mechanism on electrocatalytic carbon dioxide reduction. Chinese Chemical Letters, 2024, 35(7): 109049-. doi: 10.1016/j.cclet.2023.109049
19. [19]
  Botao Gao , He Qi , Hui Liu , Jun Chen . Role of polarization evolution in the hysteresis effect of Pb-based antiferroelecrtics. Chinese Chemical Letters, 2024, 35(4): 108598-. doi: 10.1016/j.cclet.2023.108598
20. [20]
  Xin Huang , Yi Zhao , Wanzhen Liang . Vibronic coupling effect on intersystem crossing rates of TADF emitters. Chinese Journal of Structural Chemistry, 2024, 43(6): 100278-100278. doi: 10.1016/j.cjsc.2024.100278

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(19)
HTML views(1)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142