SSK1-Loaded Neurotransmitter-Derived Nanoparticles for Alzheimer's Disease Therapy via Clearance of Senescent Cells
Wenbo Ji
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorHonglei Zhou
Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Changle Road, Qinhuai District, Nanjing, 210006 China
Search for more papers by this authorWendanqi Liang
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
School of Health Science and Engineering, University of Shanghai for Science and Technology, Jungong Road, Yangpu District, Shanghai, 200093 China
Search for more papers by this authorWeicong Zhang
School of Pharmacy, University College London, Gower Street, London, W12 8LP UK
Search for more papers by this authorBaofeng Gong
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorTong Yin
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorJianjian Chu
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorJianhua Zhuang
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorCorresponding Author
Jian Zhang
Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Clinical Pharmacy Innovatton Instttute, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Yangpu District, Shanghai, 200092 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Yi Luo
New Drug Discovery and Development, Biotheus Inc, Keji 7th Road, TangjiawanTown, Zhuhai, 519080 China
Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Clinical Pharmacy Innovatton Instttute, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Yangpu District, Shanghai, 200092 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Yan Liu
Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Clinical Pharmacy Innovatton Instttute, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Yangpu District, Shanghai, 200092 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Jie Gao
Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Changhai Road, Yangpu District, Shanghai, 200433 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
You Yin
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Jimo Road, Pudong New District, Shanghai, 200120 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorWenbo Ji
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorHonglei Zhou
Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Changle Road, Qinhuai District, Nanjing, 210006 China
Search for more papers by this authorWendanqi Liang
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
School of Health Science and Engineering, University of Shanghai for Science and Technology, Jungong Road, Yangpu District, Shanghai, 200093 China
Search for more papers by this authorWeicong Zhang
School of Pharmacy, University College London, Gower Street, London, W12 8LP UK
Search for more papers by this authorBaofeng Gong
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorTong Yin
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorJianjian Chu
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorJianhua Zhuang
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Search for more papers by this authorCorresponding Author
Jian Zhang
Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Clinical Pharmacy Innovatton Instttute, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Yangpu District, Shanghai, 200092 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Yi Luo
New Drug Discovery and Development, Biotheus Inc, Keji 7th Road, TangjiawanTown, Zhuhai, 519080 China
Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Clinical Pharmacy Innovatton Instttute, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Yangpu District, Shanghai, 200092 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Yan Liu
Department of Clinical Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Clinical Pharmacy Innovatton Instttute, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Yangpu District, Shanghai, 200092 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Jie Gao
Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Changhai Road, Yangpu District, Shanghai, 200433 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
You Yin
Department of Neurology, Second Afffliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University, Fengyang Road, Huangpu District, Shanghai, 200003 China
Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Jimo Road, Pudong New District, Shanghai, 200120 China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorAbstract
Age is a significant contributor to the onset of AD. Senolysis has been recently demonstrated to ameliorate aging-associated diseases that showing a great potential in AD therapy. However, due to the presence of BBB, the anti-AD activity of senolytics are significantly diminished. SSK1 is a prodrug that can be activated by β-gal, a lysosomal enzyme commonly upregulated in senescent cells, and thus selectively eliminates senescent cells. Furthermore, the level of β-gal is significantly correlated with conventional AD genes from clinical sequencing data. SSK1-loaded neurotransmitter -derived lipid nanoparticles are herein developed (SSK1-NPs) that revealing good BBB penetration and bioavailability of in the body. At the brain lesion, SSK1-NP treatment significantly reduces the expression of genes associated with senescence, induced senescent cells elimination, decreased amyloid-beta accumulation, and eventually improve cognitive function of aged AD mice. SSK1-NPs, a novel nanomedicine displaying potent anti-AD activity and excellent safety profile, provides a promising strategy for AD therapy.
Conflict of Interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
Research data are not shared.
Supporting Information
| Filename | Description |
|---|---|
| smll202308574-sup-0001-SuppMat.pdf789.3 KB | 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
- 1D. M. A. Oliver, P. H. Reddy, J. Alzheimer's Dis. 2019, 72, S95.
- 2Z. Arvanitakis, R. C. Shah, D. A. Bennett, JAMA, J. Am. Med. Assoc. 2019, 322, 1589.
- 3J. Skokowa, G. Cario, M. Uenalan, A. Schambach, M. Germeshausen, K. Battmer, C. Zeidler, U. Lehmann, M. Eder, C. Baum, R. Grosschedl, M. Stanulla, M. Scherr, K. Welte, Nat. Med. 2006, 12, 1191.
- 4R. A. Nixon, Nat. Med. 2013, 19, 983.
- 5P. Scheltens, K. Blennow, M. M. B. Breteler, B. de Strooper, G. B. Frisoni, S. Salloway, W. M. Van der Flier, The Lancet 2016, 388, 505.
- 6T. M. Malm, T. R. Jay, G. E. Landreth, Neurotherapeutics 2014, 12, 81.
- 7J. Chu, W. Zhang, Y. Liu, B. Gong, W. Ji, T. Yin, C. Gao, D. Liangwen, M. Hao, C. Chen, J. Zhuang, J. Gao, Y. Yin, Neural Regen. Res. 2023, 19, 100.
- 8D. Muñoz-Espín, M. Serrano, Nat. Rev. Mol. Cell Biol. 2014, 15, 482.
- 9F. Rodier, J. Campisi, J. Cell Biol. 2011, 192, 547.
- 10D. J. Baker, T. Wijshake, T. Tchkonia, N. K. LeBrasseur, B. G. Childs, B. van de Sluis, J. L. Kirkland, J. M. van Deursen, Nature 2011, 479, 232.
- 11D. J. Baker, B. G. Childs, M. Durik, M. E. Wijers, C. J. Sieben, J. Zhong, R. A. Saltness, K. B. Jeganathan, G. C. Verzosa, A. Pezeshki, K. Khazaie, J. D. Miller, J. M. van Deursen, Nature 2016, 530, 184.
- 12B. G. Childs, D. J. Baker, T. Wijshake, C. A. Conover, J. Campisi, J. M. van Deursen, Science 2016, 354, 472.
- 13M. Xu, T. Pirtskhalava, J. N. Farr, B. M. Weigand, A. K. Palmer, M. M. Weivoda, C. L. Inman, M. B. Ogrodnik, C. M. Hachfeld, D. G. Fraser, J. L. Onken, K. O. Johnson, G. C. Verzosa, L. G. P. Langhi, M. Weigl, N. Giorgadze, N. K. LeBrasseur, J. D. Miller, D. Jurk, R. J. Singh, D. B. Allison, K. Ejima, G. B. Hubbard, Y. Ikeno, H. Cubro, V. D. Garovic, X. Hou, S. J. Weroha, P. D. Robbins, L. J. Niedernhofer, et al., Nat. Med. 2018, 24, 1246.
- 14N. Musi, J. M. Valentine, K. R. Sickora, E. Baeuerle, C. S. Thompson, Q. Shen, M. E. Orr, Aging Cell 2018, 17, e12840.
- 15T. J. Bussian, A. Aziz, C. F. Meyer, B. L. Swenson, J. M. van Deursen, D. J. Baker, Nature 2018, 562, 578.
- 16P. Zhang, Y. Kishimoto, I. Grammatikakis, K. Gottimukkala, R. G. Cutler, S. Zhang, K. Abdelmohsen, V. A. Bohr, J. Misra Sen, M. Gorospe, M. P. Mattson, Nat. Neurosci. 2019, 22, 719.
- 17B. G. Childs, M. Gluscevic, D. J. Baker, R.-M. Laberge, D. Marquess, J. Dananberg, J. M. van Deursen, Nat. Rev. Drug Discovery 2017, 16, 718.
- 18M. P. Baar, R. M. C. Brandt, D. A. Putavet, J. D. D. Klein, K. W. J. Derks, B. R. M. Bourgeois, S. Stryeck, Y. Rijksen, H. van Willigenburg, D. A. Feijtel, I. van der Pluijm, J. Essers, W. A. van Cappellen, W. F. van Ijcken, A. B. Houtsmuller, J. Pothof, R. W. F. de Bruin, T. Madl, J. H. J. Hoeijmakers, J. Campisi, P. L. J. de Keizer, Cell 2017, 169, 132.
- 19Y. Zhu, E. J. Doornebal, T. Pirtskhalava, N. Giorgadze, M. Wentworth, H. Fuhrmann-Stroissnigg, L. J. Niedernhofer, P. D. Robbins, T. Tchkonia, J. L. Kirkland, Aging 2017, 9, 955.
- 20G. P. Dimri, X. Lee, G. Basile, M. Acosta, G. Scott, C. Roskelley, E. E. Medrano, M. Linskens, I. Rubelj, O. Pereira-Smith, Proc. Natl. Acad. Sci. USA 1995, 92, 9363.
- 21F. Debacq-Chainiaux, J. D. Erusalimsky, J. Campisi, O. Toussaint, Nat. Protoc. 2009, 4, 1798.
- 22B. G. Childs, M. Durik, D. J. Baker, J. M. van Deursen, Nat. Med. 2015, 21, 1424.
- 23N. E. Sharpless, C. J. Sherr, Nat. Rev. Cancer 2015, 15, 397.
- 24A. Hernandez-Segura, J. Nehme, M. Demaria, Trends Cell Biol. 2018, 28, 436.
- 25V. Gorgoulis, P. D. Adams, A. Alimonti, D. C. Bennett, O. Bischof, C. Bishop, J. Campisi, M. Collado, K. Evangelou, G. Ferbeyre, J. Gil, E. Hara, V. Krizhanovsky, D. Jurk, A. B. Maier, M. Narita, L. Niedernhofer, J. F. Passos, P. D. Robbins, C. A. Schmitt, J. Sedivy, K. Vougas, T. von Zglinicki, D. Zhou, M. Serrano, M. Demaria, Cell 2019, 179, 813.
- 26Y. Cai, H. Zhou, Y. Zhu, Q. Sun, Y. Ji, A. Xue, Y. Wang, W. Chen, X. Yu, L. Wang, H. Chen, C. Li, T. Luo, H. Deng, Cell Res. 2020, 30, 574.
- 27S. Tarantini, P. Balasubramanian, J. Delfavero, T. Csipo, A. Yabluchanskiy, T. Kiss, Á. Nyúl-Tóth, P. Mukli, P. Toth, C. Ahire, A. Ungvari, Z. Benyo, A. Csiszar, Z. Ungvari, GeroScience 2021, 43, 2427.
- 28W. M. Pardridge, Drug Discovery Today 2007, 12, 54.
- 29T. M. Barchet, M. M. Amiji, Expert Opin. Drug Deliv. 2009, 6, 211.
- 30P. Y. Collins, V. Patel, S. S. Joestl, D. March, T. R. Insel, A. S. Daar, I. A. Bordin, E. J. Costello, M. Durkin, C. Fairburn, R. I. Glass, W. Hall, Y. Huang, S. E. Hyman, K. Jamison, S. Kaaya, S. Kapur, A. Kleinman, A. Ogunniyi, A. Otero-Ojeda, M. M. Poo, V. Ravindranath, B. J. Sahakian, S. Saxena, P. A. Singer, D. J. Stein, W. Anderson, M. A. Dhansay, W. Ewart, A. Phillips, et al., Nature 2011, 475, 27.
- 31B. Obermeier, R. Daneman, R. M. Ransohoff, Nat. Med. 2013, 19, 1584.
- 32O. Khorkova, C. Wahlestedt, Nat. Biotechnol. 2017, 35, 249.
- 33M. M. Patel, B. M. Patel, CNS Drugs 2017, 31, 109.
- 34X. Dong, Theranostics 2018, 8, 1481.
- 35L. K. Fung, M. Shin, B. Tyler, H. Brem, W. M. Saltzman, Pharm. Res. 1996, 13, 671.
- 36J. L. Rubenstein, J. Fridlyand, L. Abrey, A. Shen, J. Karch, E. Wang, S. Issa, L. Damon, M. Prados, M. McDermott, J. O'Brien, C. Haqq, M. Shuman, J. Clin. Oncol. 2007, 25, 1350.
- 37C. T. Lu, Y. Z. Zhao, H. L. Wong, J. Cai, L. Peng, X. Q. Tian, Int. J. Nanomed. 2014, 9, 2241.
- 38K. Villringer, B. E. Sanz Cuesta, A.-C. Ostwaldt, U. Grittner, P. Brunecker, A. A. Khalil, K. Schindler, O. Eisenblätter, H. Audebert, J. B. Fiebach, Neurology 2016, 88, 433.
- 39B. Bukari, R. M. Samarasinghe, J. Noibanchong, S. L. Shigdar, Biomedicines 2020, 8, 120.
- 40Y. Zhou, Z. Peng, E. S. Seven, R. M. Leblanc, J. Controlled Release 2018, 270, 290.
- 41E. Blanco, H. Shen, M. Ferrari, Nat. Biotechnol. 2015, 33, 941.
- 42J. Wen, D. Wu, M. Qin, C. Liu, L. Wang, D. Xu, H. V. Vinters, Y. Liu, E. Kranz, X. Guan, G. Sun, X. Sun, Y. Lee, O. Martinez-Maza, D. Widney, Y. Lu, I. S. Y. Chen, M. Kamata, Nat. Biomed. Eng. 2019, 3, 706.
- 43F. Ma, L. Yang, Z. Sun, J. Chen, X. Rui, Z. Glass, Q. Xu, Sci. Adv. 2020, 6, eabb4429.
- 44S. Zhang, Y. Li, X. Qiu, A. Jiao, W. Luo, X. Lin, X. Zhang, Z. Zhang, J. Hong, P. Cai, Bioact. Mater. 2021, 006.
- 45M. Wang, J. A. Zuris, F. Meng, H. Rees, S. Sun, P. Deng, Y. Han, X. Gao, D. Pouli, Q. Wu, I. Georgakoudi, D. R. Liu, Q. Xu, Proc. Natl. Acad. Sci. USA 2016, 113, 2868.
- 46J. Chang, X. Chen, Z. Glass, F. Gao, L. Mao, M. Wang, Q. Xu, Acc. Chem. Res. 2018, 52, 665.
- 47M. Wang, K. Alberti, S. Sun, C. L. Arellano, Q. Xu, Angew. Chem., Int. Ed. 2014, 53, 2893.
- 48S. Ding, N. Anton, T. F. Vandamme, C. A. Serra, Exp. Opin Drug Deliv. 2016, 13, 1447.
- 49P. I. P. Soares, A. I. Sousa, J. C. Silva, I. M. M. Ferreira, C. M. M. Novo, J. P. Borges, Carbohydr. Polym. 2016, 147, 304.
- 50F. Liu, L. Yang, Y. Li, A. Junier, F. Ma, J. Chen, H. Han, Z. Glass, X. Zhao, C. A. Kumamoto, H. Sang, Q. Xu, ACS Biomater. Sci. Eng. 2020, 6, 1064.
- 51L. Pang, H. Jin, Z. Lu, F. Xie, H. Shen, X. Li, X. Zhang, X. Jiang, L. Wu, M. Zhang, T. Zhang, Y. Zhai, Y. Zhang, H. Guan, J. Su, M. Li, J. Gao, Adv. Healthcare Mater. 2023, 12, 2300315.
- 52F. Szabc, D. Fxa, E. Kl, Z. A. He, Y. I. You, Y. A. Yuan, A. Gl, G. Sz, W. C. Yan, X. C. Ke, Acta Pharm. Sin. B 2022, 12, 15.
- 53X. Xue, H. Liu, S. Wang, Y. Hu, B. Huang, M. Li, J. Gao, X. Wang, J. Su, Compos., Part B. Eng. 2022, 237.
- 54K. Zheng, Y. Tong, S. Zhang, R. He, Y. Li, Adv. Funct. Mater. 2021, 31, 2102599.
- 55P. I. Deryabin, A. N. Shatrova, A. V. Borodkina, Cell. Mol. Life Sci. 2021, 78, 7757.
- 56A. Habiro, S. Tanno, K. Koizumi, T. Izawa, Y. Nakano, M. Osanai, Y. Mizukami, T. Okumura, Y. Kohgo, Biochem. Biophys. Res. Commun. 2004, 316, 71.
- 57K. Koizumi, S. Tanno, Y. Nakano, A. Habiro, T. Izawa, Y. Mizukami, T. Okumura, Y. Kohgo, Anticancer Res. 2005, 25, 3347.
- 58N. S. Gasek, G. A. Kuchel, J. L. Kirkland, M. Xu, Nat. Aging 2021, 1, 870.
- 59Y. Mizuno, N. Abolhassani, G. Mazzei, K. Sakumi, T. Saito, T. C. Saido, T. Ninomiya, T. Iwaki, R. Yamasaki, J.-I. Kira, Y. Nakabeppu, Oxidative Med. Cell. Longev. 2021, 2021, 8635088.
- 60Y. Gao, J. Liu, J. Wang, Y. Liu, L. H. Zeng, W. Ge, C. Ma, Brain Pathol. 2022, 32, e1304.
10.1111/bpa.13047 Google Scholar
- 61S. Oddo, A. Caccamo, J. D. Shepherd, M. P. Murphy, T. E. Golde, R. Kayed, R. Metherate, M. P. Mattson, Y. Akbari, F. M. LaFerla, Neuron 2003, 39, 409.
- 62Y. Saito, T. S. Chikenji, Front. Pharmacol. 2021, 12, 739510.
- 63S. Mourtas, A. N. Lazar, E. Markoutsa, C. Duyckaerts, S. G. Antimisiaris, Eur. J. Med. Chem. 2014, 80, 175.
- 64Y. C. Kuo, Y. I. Lou, R. Rajesh, J. Drug Target 2020, 28, 949.
- 65G. Veerman, V. W. T. R. van Haperen, J. B. Vermorken, P. Noordhuis, B. J. M. Braakhuis, H. M. Pinedo, G. J. Peters, Cancer Chemother. Pharmacol. 1996, 38, 335.
- 66X. M. Li, K. Tanaka, J. Sun, E. Filipski, L. Kayitalire, C. Focan, F. Lévi, Br. J. Cancer 2005, 92, 1684.
