Unconventional PROTACs for Targeted Protein Degradation in Cancer Therapy
Xu Zhang
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 P.R. China
Search for more papers by this authorZhangzhi Song
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 P.R. China
Search for more papers by this authorXinyu Zhang
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 P.R. China
Search for more papers by this authorCorresponding Author
Jianhua Zou
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074 Singapore
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599 Singapore
Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597 Singapore
Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667 Singapore
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Guocan Yu
Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084 P.R. China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Xiaoyuan Chen
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074 Singapore
Department of Chemical and Biomolecular Engineering, College of Design and Engineering, National University of Singapore, Singapore, 117575 Singapore
Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, 117575 Singapore
Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, 117544 Singapore
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599 Singapore
Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597 Singapore
Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667 Singapore
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, 138673 Singapore
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Sheng Wang
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 P.R. China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorXu Zhang
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 P.R. China
Search for more papers by this authorZhangzhi Song
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 P.R. China
Search for more papers by this authorXinyu Zhang
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 P.R. China
Search for more papers by this authorCorresponding Author
Jianhua Zou
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074 Singapore
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599 Singapore
Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597 Singapore
Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667 Singapore
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Guocan Yu
Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084 P.R. China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Xiaoyuan Chen
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074 Singapore
Department of Chemical and Biomolecular Engineering, College of Design and Engineering, National University of Singapore, Singapore, 117575 Singapore
Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, 117575 Singapore
Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore, 117544 Singapore
Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599 Singapore
Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597 Singapore
Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667 Singapore
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore, 138673 Singapore
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Sheng Wang
School of Life Sciences, Faculty of Medicine, Tianjin University, Tianjin, 300072 P.R. China
E-mail: [email protected]; [email protected]; [email protected]; [email protected]
Search for more papers by this authorGraphical Abstract
To overcome the challenges of conventional proteolysis-targeting chimeras (PROTACs), various “unconventional PROTACs” including PROTACs with unconventional binding ligands, PROTACs with unconventional linkers, pro-PROTACs, and self-assembled PROTACs have been proposed. These unconventional PROTACs show great promise for targeted protein degradation in cancer therapy. This review summarizes recent advances in the development of unconventional PROTACs.
Abstract
Targeted protein degradation, which aims to eliminate dysregulated proteins, has emerged as a promising strategy for conquering challenging therapeutic targets. Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule that utilizes the ubiquitin-proteasome system to selectively degrade target proteins. Due to its ability to degrade “undruggable” proteins without causing drug resistance, PROTAC has shown great potential in innovative drug development, especially in cancer therapy. However, conventional PROTACs suffer from several limitations, such as limited solubility, poor permeability, hook effect, and off-target toxicity. Therefore, structural innovation of conventional PROTACs to make them meet the therapeutic demand is essential for unlocking the full potential of PROTACs as a therapeutic tool. Here, we summarize four types of unconventional PROTACs for addressing the above challenges and enhancing cancer therapy efficacy, including PROTACs with unconventional binding ligands, PROTACs with unconventional linkers, pro-PROTACs, and self-assembled PROTACs. These optimized designs contribute to the development of PROTACs-based universal platforms, providing directions for innovative drug developments and expanding the applications of PROTACs in cancer therapy.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
References
- 1Y. Liu, X. Zhang, X. Zhang, G. Wang, X. Li, S. Xing, C. Cao, Y. Li, L. Han, S. Wang, Int. J. Biol. Macromol. 2025, 305, 141184.
- 2X. Zhang, X. Zhang, Q. Fan, J. Li, S. Jia, X. Chen, S. Wang, Small 2025, 21, e2408156.
- 3S. Chen, X. Zhang, H. Li, C. Cao, X. Zhang, J. Li, S. Jia, Y. Liu, L. Han, S. Wang, Int. J. Pharm. 2024, 663, 124568.
- 4J. Zhou, C. Cao, X. Zhang, X. Zhang, J. Li, H. Deng, S. Wang, J. Controlled Release 2023, 360, 564–577.
- 5S. Xing, X. Zhang, H. Guo, S. Jia, S. Xu, Y. Liu, X. Li, Y. Li, S. Wang, ACS Appl. Nano Mater. 2025, 8, 3558–3565.
- 6J. Li, C. Cao, X. Zhang, X. Zhang, S. Wang, Biomaterials 2025, 317, 123106–123106.
- 7J. Wang, H. Ding, Y. Zhu, Y. Liu, M. Yu, H. Cai, R. Ao, H. Huang, P. Gong, Y. Liao, Z. Chen, L. Lin, X. Chen, H. Yang, Angew. Chem. Int. Ed. 2023, 62, e202302255.
- 8L. Zhao, J. Zhao, K. Zhong, A. Tong, D. Jia, Signal Transduction Targeted Ther.. 2022, 7, 113.
- 9J. Zheng, W. He, J. Li, X. Feng, Y. Li, B. Cheng, Y. Zhou, M. Li, K. Liu, X. Shao, J. Zhang, H. Li, L. Chen, L. Fang, J. Am. Chem. Soc. 2022, 144, 21831–21836.
- 10K. M. Sakamoto, K. B. Kim, A. Kumagai, F. Mercurio, C. M. Crews, R. J. Deshaies, Proc. Natl. Acad. Sci. USA 2001, 98, 8554–8559.
- 11K. Li, C. M. Crews, Chem. Soc. Rev. 2022, 51, 5214–5236.
- 12Z. Lin, B. A. Garcia, D. Lv, Angew. Chem. Int. Ed. 2024, 63, e202316581.
- 13G. M. Burslem, C. M. Crews, Cell 2020, 181, 102–114.
- 14J. Kim, I. Byun, D. Y. Kim, H. Joh, H. J. Kim, M. J. Lee, Chem. Soc. Rev. 2024, 53, 3253–3272.
- 15Y. He, S. Khan, Z. Huo, D. Lv, X. Zhang, X. Liu, Y. Yuan, R. Hromas, M. Xu, G. Zheng, D. Zhou, J. Hematol. Oncol. 2020, 13, 103.
- 16C. Wang, Y. Zhang, W. Chen, Y. Wu, D. Xing, Mol. Cancer 2024, 23, 110.
- 17M. Lv, W. Hu, S. Zhang, L. He, C. Hu, Cancer Lett. 2022, 539, 215716.
- 18L. Bai, H. Zhou, R. Xu, Y. Zhao, K. Chinnaswamy, D. McEachern, J. Chen, C.-Y. Yang, Z. Liu, M. Wang, L. Liu, H. Jiang, B. Wen, P. Kumar, J. L. Meagher, D. Sun, J. A. Stuckey, S. Wang, Cancer Cell 2019, 36, 498–511.
- 19Y. Li, J. Song, P. Zhou, J. Zhou, S. Xie, J. Med. Chem. 2022, 65, 10183–10194.
- 20X. Yao, J. Mao, H. Zhang, Y. Xiao, Y. Wang, H. Liu, Eur. J. Med. Chem. 2024, 272, 116488.
- 21J. Ma, L. Fang, Z. Sun, M. Li, T. Fan, G. Xiang, X. Ma, Adv. Healthcare Mater. 2024, 13, 2400109.
- 22X. Sun, H. Gao, Y. Yang, M. He, Y. Wu, Y. Song, Y. Tong, Y. Rao, Signal Transduction Targeted Ther.. 2019, 4, 64.
- 23A. Ocana, A. Pandiella, J. Exp. Clin. Cancer Res. 2020, 39, 189.
- 24S. D. Kaur, N. Bedi, D. Kumar, D. N. Kapoor, Cancer Lett. 2023, 556, 216065.
- 25Z. Li, G. Ren, X. Wang, X. Li, L. Ding, J. Zhu, Y. Zhang, C. Zhang, J. Zou, X. Chen, Biomaterials 2025, 322, 123387.
- 26R. Huang, Y. Hu, Y.-F. Wang, S. Zhang, Z.-G. Wang, D.-W. Pang, S.-L. Liu, Angew. Chem. Int. Ed. 2025, 64, e202423524.
- 27Y. Liu, X. Yang, Y. Wang, Y. Yang, D. Sun, H. Li, L. Chen, Eur. J. Med. Chem. 2021, 214, 113264.
- 28F. Wang, Y. Zhan, M. Li, L. Wang, A. Zheng, C. Liu, H. Wang, T. Wang, ACS Pharmacol. Transl. Sci. 2023, 6, 76–87.
- 29C. Zhu, Z. Yang, Y. Zhang, Z. Li, G. Li, B. Yang, N. Kang, J. Wang, Y. Sun, N. Ding, Y. Rao, W. Liu, Cell Discov. 2024, 10, 82.
- 30W. Wang, Q. Zhou, T. Jiang, S. Li, J. Ye, J. Zheng, X. Wang, Y. Liu, M. Deng, D. Ke, Q. Wang, Y. Wang, J.-Z. Wang, Theranostics 2021, 11, 5279–5295.
- 31C. Wang, Y. Zhang, S. Yang, D. Xing, Arabian J. Chem. 2023, 16, 105015.
- 32L. Qu, S. Li, L. Ji, S. Luo, M. Ding, F. Yin, C. Wang, H. Luo, D. Lu, X. Liu, W. Peng, L. Kong, X. Wang, Eur. J. Med. Chem. 2021, 226, 113889.
- 33B. Gong, W. Zhang, W. Cong, Y. Gu, W. Ji, T. Yin, H. Zhou, H. Hu, J. Zhuang, Y. Luo, Y. Liu, J. Gao, Y. Yin, Adv. Healthcare Mater. 2024, 13, 2400149.
- 34J.-h. Huang, C.-j. Huang, L.-n. Yu, X.-l. Guan, S.-w. Liang, J.-h. Li, L. Liang, M.-y. Wei, L.-m. Zhang, Acta Pharmacol. Sin. 2023, 44, 1962–1976.
- 35L. Liu, C. Yang, B. P. Lavayen, R. J. Tishko, J. Larochelle, E. Candelario-Jalil, J. Neuroinflammation 2022, 19, 168.
- 36D. Li, Y. Deng, G. Wen, L. Wang, X. Shi, S. Chen, R. Chen, Int. Immunopharmacol. 2024, 132, 111991.
- 37J. Wu, L. Li, Q. Zhu, T. Zhang, F. Miao, Z. Cui, G. Dong, Z. Tai, Z. Chen, Biomed. Pharmacother. 2024, 171, 116167.
- 38D. Chirnomas, K. R. Hornberger, C. M. Crews, Nat. Rev. Clin. Oncol. 2023, 20, 265–278.
- 39X. Li, Y. Song, J. Hematol. Oncol. 2020, 13, 50.
- 40H. Gao, X. Sun, Y. Rao, ACS Med. Chem. Lett. 2020, 11, 237–240.
- 41M. Wu, Y. Zhao, C. Zhang, K. Pu, ACS Nano 2024, 18, 28502–28530.
- 42Y. Chen, I. Tandon, W. Heelan, Y. Wang, W. Tang, Q. Hu, Chem. Soc. Rev. 2022, 51, 5330–5350.
- 43L. Guo, Y. Zhou, X. Nie, Z. Zhang, Z. Zhang, C. Li, T. Wang, W. Tang, Eur. J. Med. Chem. 2022, 236, 114317.
- 44S. Wang, Z. Feng, C. Qu, S. Yu, H. Zhang, R. Deng, D. Luo, C. Pu, Y. Zhang, R. Li, J. Med. Chem. 2024, 67, 9842–9856.
- 45D. Huang, Y. Zou, H. Huang, J. Yin, S. Long, W. Sun, J. Du, J. Fan, X. Chen, X. Peng, Adv. Mater. 2024, 36, 2313460.
- 46H. Zhu, J. Wang, Q. Zhang, X. Pan, J. Zhang, Pharmacol. Ther. 2023, 244, 108371.
- 47M. Schapira, M. F. Calabrese, A. N. Bullock, C. M. Crews, Nat. Rev. Drug Discovery 2019, 18, 949–963.
- 48X. Li, W. Pu, Q. Zheng, M. Ai, S. Chen, Y. Peng, Mol. Cancer 2022, 21, 99.
- 49Y. Li, Y. Wu, S. Gao, T. Sun, C. Jiang, J. Controlled Release 2025, 378, 116–144.
- 50X. Han, Y. Sun, Medcomm 2023, 4, e290.
- 51Z. Liu, M. Hu, Y. Yang, C. Du, H. Zhou, C. Liu, Y. Chen, L. Fan, H. Ma, Y. Gong, Y. Xie, Mol. Biomed. 2022, 3, 46.
- 52C. Wang, Y. Zhang, W. Yu, J. Xu, D. Xing, Int. J. Biol. Macromol. 2024, 261, 129864.
- 53J. Liu, H. Chen, L. Ma, Z. He, D. Wang, Y. Liu, Q. Lin, T. Zhang, N. Gray, H. U. Kaniskan, J. Jin, W. Wei, Sci. Adv. 2020, 6, eaay5154.
- 54J. Li, X. Chen, A. Lu, C. Liang, Innovation 2023, 4, 100413.
- 55S. Ma, J. Ji, Y. Tong, Y. Zhu, J. Dou, X. Zhang, S. Xu, T. Zhu, X. Xu, Q. You, Z. Jiang, Acta Pharm. Sin. B 2022, 12, 2990–3005.
- 56L. Ou, M. T. Setegne, J. Elliot, F. Shen, L. M. K. Dassama, Chem. Rev. 2025.
- 57X. Huang, F. Wu, J. Ye, L. Wang, X. Wang, X. Li, G. He, Acta Pharm. Sin. B 2024, 14, 2402–2427.
- 58L. Fan, W. Tong, A. Wei, X. Mu, Int. J. Biol. Macromol. 2024, 275, 133680.
- 59J. Liu, Y. Liu, J. Tang, Q. Gong, G. Yan, H. Fan, X. Zhang, C. Pu, Eur. J. Med. Chem. 2024, 279, 116901.
- 60C. Chen, Y. Yang, Z. Wang, H. Li, C. Dong, X. Zhang, J. Med. Chem. 2023, 66, 8428–8440.
- 61L. Yao, N. Yang, W. Zhou, M. H. Akhtar, W. Zhou, C. Liu, S. Song, Y. Li, W. Han, C. Yu, Adv. Healthcare Mater. 2023, 12, 2300871.
- 62C. Zhang, Z. Zeng, D. Cui, S. He, Y. Jiang, J. Li, J. Huang, K. Pu, Nat. Commun. 2021, 12, 2934.
- 63N.-Y. Zhang, D.-Y. Hou, X.-J. Hu, J.-X. Liang, M.-D. Wang, Z.-Z. Song, L. Yi, Z.-J. Wang, H.-W. An, W. Xu, H. Wang, Angew. Chem. Int. Ed. 2023, 62, e202308049.
- 64E. Varfolomeev, J. W. Blankenship, S. M. Wayson, A. V. Fedorova, N. Kayagaki, P. Garg, K. Zobel, J. N. Dynek, L. O. Elliott, H. J. A. Wallweber, J. A. Flygare, W. J. Fairbrother, K. Deshayes, V. M. Dixit, D. Vucic, Cell 2007, 131, 669–681.
- 65S. Benjamin, H. Steller, Dev. Cell 2010, 19, 791–792.
- 66J. Huang, X. Fu, F. Qiu, Z. Liang, C. Cao, Z. Wang, H. Chen, S. Yue, D. Xie, Y. Liang, A. Lu, C. Liang, J. Am. Chem. Soc. 2024, 147, 1920–1937.
- 67A. R. Schneekloth, M. Pucheault, H. S. Tae, C. M. Crews, Bioorg. Med. Chem. Lett. 2008, 18, 5904–5908.
- 68N. J. Henning, A. G. Manford, J. N. Spradlin, S. M. Brittain, E. Zhang, J. M. McKenna, J. A. Tallarico, M. Schirle, M. Rape, D. K. Nomura, J. Am. Chem. Soc. 2022, 144, 701–708.
- 69F. Feller, I. Honin, M. Miranda, H. Weber, S. Henze, M. Hanl, F. K. Hansen, J. Med. Chem. 2025, 68, 1824–1843.
- 70X. Zhang, L. M. Luukkonen, C. L. Eissler, V. M. Crowley, Y. Yamashita, M. A. Schafroth, S. Kikuchi, D. S. Weinstein, K. T. Symons, B. E. Nordin, J. L. Rodriguez, T. G. Wucherpfennig, L. G. Bauer, M. M. Dix, D. Stamos, T. M. Kinsella, G. M. Simon, K. A. Baltgalvis, B. F. Cravatt, J. Am. Chem. Soc. 2021, 143, 5141–5149.
- 71X. Zhang, V. M. Crowley, T. G. Wucherpfennig, M. M. Dix, B. F. Cravatt, Nat. Chem. Biol. 2019, 15, 737–746.
- 72C. C. Ward, J. I. Kleinman, S. M. Brittain, P. S. Lee, C. Y. S. Chung, K. Kim, Y. Petri, J. R. Thomas, J. A. Tallarico, J. M. McKenna, M. Schirle, D. K. Nomura, ACS Chem. Biol. 2019, 14, 2430–2440.
- 73J. N. Spradlin, X. Hu, C. C. Ward, S. M. Brittain, M. D. Jones, L. Ou, M. To, A. Proudfoot, E. Ornelas, M. Woldegiorgis, J. A. Olzmann, D. E. Bussiere, J. R. Thomas, J. A. Tallarico, J. M. McKenna, M. Schirle, T. J. Maimone, D. K. Nomura, Nat. Chem. Biol. 2019, 15, 747–755.
- 74J. Lee, Y. Lee, Y. M. Jung, J. H. Park, H. S. Yoo, J. Park, Molecules 2022, 27, 6515.
- 75C. Zhang, Y. Liu, G. Li, Z. Yang, C. Han, X. Sun, C. Sheng, K. Ding, Y. Rao, Sci. Bull. 2024, 69, 1776–1797.
- 76J. Liu, H. Chen, H. U. Kaniskan, L. Xie, X. Chen, J. Jin, W. Wei, J. Am. Chem. Soc. 2021, 143, 8902–8910.
- 77J. Shao, Y. Yan, D. Ding, D. Wang, Y. He, Y. Pan, W. Yan, A. Kharbanda, H.-y. Li, H. Huang, Adv. Sci. 2021, 8, 2102555.
- 78Z. Wang, J. Liu, H. Chen, X. Qiu, L. Xie, H. U. Kaniskan, X. Chen, J. Jin, W. Wei, J. Am. Chem. Soc. 2023, 145, 10872–10879.
- 79X. Li, Z. Zhang, F. Gao, Y. Ma, D. Wei, Z. Lu, S. Chen, M. Wang, Y. Wang, K. Xu, R. Wang, F. Xu, J.-Y. Chen, C. Zhu, Z. Li, H. Yu, X. Guan, J. Am. Chem. Soc. 2023, 145, 9334–9342.
- 80Y. Wang, G. Yang, X. Zhang, R. Bai, D. Yuan, D. Gao, Q. He, Y. Yuan, X. Zhang, J. Kou, L. Zheng, Y. Huang, Z. Tang, Y. Bao, X. Song, Y. Zhao, Adv. Sci. 2024, 11, 2309639
- 81J. Xu, X. Zhao, X. Liang, D. Guo, J. Wang, Q. Wang, X. Tang, Sci. Adv. 2024, 10, eadp0334–eadp0334.
- 82R. Peng, Q. Huang, L. Wang, G. Qiao, X. Huang, J. Jiang, X. Chu, Angew. Chem. Int. Ed. 2024, 63, e202402715.
- 83Y. Moon, H. Cho, J. Kim, S. Song, J. Y. Park, J. Y. Min, E. H. Han, Y. Kim, J.-K. Seong, M. K. Shim, K. Kim, Angew. Chem. Int. Ed. 2024, 64, e202414146.
- 84X. Lu, J. Jin, Y. Wu, J. Lin, X. Zhang, S. Lu, J. Zhang, C. Zhang, M. Ren, H. Chen, W. Zhang, X. Luan, Bioact. Mater. 2025, 43, 255–272.
- 85B. Ma, D. Liu, M. Zheng, Z. Wang, D. Zhang, Y. Jian, J. Ma, Y. Fan, Y. Chen, Y. Gao, J. Liu, X. Li, L. Li, JACS Au 2024, 4, 816–827.
- 86Y. Zhang, J. Luo, X. Gui, Y. Zheng, E. Schaar, G. Liu, J. Shi, J. Controlled Release 2023, 364, 124–141.
- 87V. C. Vetter, E. Wagner, J. Controlled Release 2022, 346, 110–135.
- 88Z. Zhang, J. Conniot, J. Amorim, Y. Jin, R. Prasad, X. Yan, K. Fan, J. Conde, J. Controlled Release 2022, 350, 80–92.
- 89S. G. Huayamares, D. Loughrey, H. Kim, J. E. Dahlman, E. J. Sorscher, Nat. Rev. Clin. Oncol. 2024, 21, 407–427.
- 90W. Wang, S. He, G. Dong, C. Sheng, J. Med. Chem. 2022, 65, 10217–10232.
- 91A. Ghidini, A. Clery, F. Halloy, F. H. T. Allain, J. Hall, Angew. Chem. Int. Ed. 2021, 60, 3163–3169.
- 92J. Fetse, S. Kandel, U.-F. Mamani, K. Cheng, Trends Pharmacol. Sci. 2023, 44, 425–441.
- 93M. Muttenthaler, G. E. King, D. J. Adams, P. E. Alewood, Nat. Rev. Drug Discovery 2021, 20, 309–325.
- 94A. Mullard, Nat. Rev. Drug Discovery 2023, 22, 615–616.
- 95K. Sharma, K. K. Sharma, A. Sharma, R. Jain, Drug Discovery Today 2023, 28, 1–15.
- 96K. Vrbnjak, R. N. Sewduth, Pharmaceutics 2024, 16, 1486.
- 97J. Jin, Y. Wu, J. Chen, Y. Shen, L. Zhang, H. Zhang, L. Chen, H. Yuan, H. Chen, W. Zhang, X. Luan, Theranostics 2020, 10, 10141–10153.
- 98K. Wang, X. Dai, A. Yu, C. Feng, K. Liu, L. Huang, J. Exp. Clin. Cancer Res. 2022, 41, 289.
- 99H. Liao, X. Li, L. Zhao, Y. Wang, X. Wang, Y. Wu, X. Zhou, W. Fu, L. Liu, H.-G. Hu, Y.-G. Chen, Cell Discov. 2020, 6, 35.
- 100J. H. Park, H. van Wyk, D. C. McMillan, J. Quinn, J. Clark, C. S. D. Roxburgh, P. G. Horgan, J. Edwards, Clin. Cancer Res. 2017, 23, 1698–1709.
- 101A. Malki, R. Abu ElRuz, I. Gupta, A. Allouch, S. Vranic, A.-E. Al Moustafa, Int. J. Mol. Sci. 2021, 22, 130.
- 102B. Ma, Y. Fan, D. Zhang, Y. Wei, Y. Jian, D. Liu, Z. Wang, Y. Gao, J. Ma, Y. Chen, S. Xu, L. Li, Adv. Sci. 2022, 9, 2201859.
- 103D. Zhang, B. Ma, D. Liu, W. Wu, T. Zhou, Y. Gao, C. Yang, Y. Jian, Y. Fan, Y. Qian, J. Ma, Y. Gao, Y. Chen, S. Xu, L. Li, Ebiomedicine 2024, 105, 105212.
- 104I. W. Hamley, Chem. Rev. 2017, 117, 14015–14041.
- 105E. Ruoslahti, Adv. Drug Delivery Rev. 2017, 110–111, 3–12.
- 106Y.-Y. Shi, G. Fan, R. Tan, S. Li, H.-B. Sun, R. Li, M. Yang, S. Gao, M. Liu, M.-Y. Dai, Cell Death Dis.. 2024, 15, 701.
- 107Q.-x. Huang, D.-m. Fan, Z.-z. Zheng, T. Ran, A. Bai, R.-q. Xiao, G.-s. Hu, W. Liu, J. Med. Chem. 2024, 67, 6658–6672.
- 108S. He, Y. Fang, M. Wu, P. Zhang, F. Gao, H. Hu, C. Sheng, G. Dong, J. Med. Chem. 2023, 66, 16828–16842.
- 109J. W. Li, G. Zheng, F. J. Kaye, L. Wu, Mol. Ther. 2023, 31, 647–656.
- 110M. Zheng, J. Huo, X. Gu, Y. Wang, C. Wu, Q. Zhang, W. Wang, Y. Liu, Y. Liu, X. Zhou, L. Chen, Y. Zhou, H. Li, J. Med. Chem. 2021, 64, 7839–7852.
- 111L. Xin, C. Wang, Y. Cheng, H. Wang, X. Guo, X. Deng, X. Deng, B. Xie, H. Hu, C. Min, C. Dong, H.-B. Zhou, J. Med. Chem. 2024, 67, 8913–8931.
- 112S. Imaide, K. M. Riching, N. Makukhin, V. Vetma, C. Whitworth, S. J. Hughes, N. Trainor, S. D. Mahan, N. Murphy, A. D. Cowan, K.-H. Chan, C. Craigon, A. Testa, C. Maniaci, M. Urh, D. L. Daniels, A. Ciulli, Nat. Chem. Biol. 2021, 17, 1157–1167.
- 113A. G. Bond, M. Ordono, C. M. Bisbach, C. Craigon, N. Makukhin, E. A. Caine, M. Nagala, M. Urh, G. E. Winter, K. M. Riching, A. Ciulli, J. Am. Chem. Soc. 2024, 146, 33675–33711.
- 114Y. Chen, Z. Xia, U. Suwal, P. Rappu, J. Heino, O. De Wever, B. G. De Geest, Chem. Sci. 2024, 15, 17691–17701.
- 115C. Song, Z. Jiao, Z. Hou, R. Wang, C. Lian, Y. Xing, Q. Luo, Y. An, F. Yang, Y. Wang, X. Sha, Z. Ruan, Y. Ye, Z. Liu, Z. Li, F. Yin, J. Am. Chem. Soc. 2023, 145, 21860–21870.
- 116C. Song, Z. Jiao, Z. Hou, Y. Xing, X. Sha, Y. Wang, J. Chen, S. Liu, Z. Li, F. Yin, JACS Au 2024, 4, 2915–2924.
- 117W. Su, M. Tan, Z. Wang, J. Zhang, W. Huang, H. Song, X. Wang, H. Ran, Y. Gao, G. Nie, H. Wang, Angew. Chem. Int. Ed. 2023, 62, e202218128.
- 118Z. Wang, M. Tan, W. Su, W. Huang, J. Zhang, F. Jia, G. Cao, X. Liu, H. Song, H. Ran, G. Nie, H. Wang, J. Med. Chem. 2023, 66, 6263–6273.
- 119L. Zhou, B. Yu, M. Gao, R. Chen, Z. Li, Y. Gu, J. Bian, Y. Ma, Nat. Commun. 2023, 14, 4510.
- 120S. Li, T. Zeng, Z. Wu, J. Huang, X. Cao, Y. Liu, S. Bai, Q. Chen, C. Li, C. Lu, H. Yang, J. Am. Chem. Soc. 2025, 147, 2168–2181.
- 121X. Li, X. Li, F. Liu, S. Li, D. Shi, J. Med. Chem. 2021, 64, 10581–10605.
- 122R. Morphy, C. Kay, Z. Rankovic, Drug Discovery Today 2004, 9, 641–651.
- 123A. Cavalli, M. L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti, M. Recanatini, C. Melchiorre, J. Med. Chem. 2008, 51, 347–372.
- 124M. Bekes, D. R. Langley, C. M. Crews, Nat. Rev. Drug Discovery 2022, 21, 181–200.
- 125J. van der Veeken, S. Oliveira, R. M. Schiffelers, G. Storm, P. M. P. v. B. E. Henegouwen, R. C. Roovers, Curr. Cancer Drug Targets 2009, 9, 748–760.
- 126F. Morgillo, H. Y. Lee, Drug Resist. Updates 2005, 8, 298–310.
- 127A. Anighoro, J. Bajorath, G. Rastelli, J. Med. Chem. 2014, 57, 7874–7887.
- 128J. J. Wright, Clin. Cancer Res. 2010, 16, 4094–4104.
- 129R. E. Kontermann, mAbs 2012, 4, 182–197.
- 130J. Ye, J. Wu, B. Liu, Biochim. Biophys. Acta, Rev. Cancer 2023, 1878, 188866.
- 131J.-Y. Lin, H.-J. Liu, Y. Wu, J.-M. Jin, Y.-D. Zhou, H. Zhang, D. G. Nagle, H.-Z. Chen, W.-D. Zhang, X. Luan, Small 2023, 19, 2207778.
- 132T. Luo, Q. Zheng, L. Shao, T. Ma, L. Mao, M. Wang, Angew. Chem. Int. Ed. 2022, 61, e202206277.
- 133H.-T. Zhang, R. Peng, S. Chen, A. Shen, L. Zhao, W. Tang, X.-H. Wang, Z.-Y. Li, Z.-G. Zha, M. Yi, L. Zhang, Adv. Sci. 2022, 9, 2202039.
- 134H.-J. Liu, W. Chen, G. Wu, J. Zhou, C. Liu, Z. Tang, X. Huang, J. Gao, Y. Xiao, N. Kong, N. Joshi, Y. Cao, R. Abdi, W. Tao, Adv. Sci. 2023, 10, 2207439.
- 135J. Chen, F. Ma, Y. Zhang, M. Xu, L. Xu, Y. Liu, R. Ma, L. Shi, Adv. Funct. Mater. 2024, 34, 2314203.
- 136D. Rosenblum, N. Joshi, W. Tao, J. M. Karp, D. Peer, Nat. Commun. 2018, 9, 1410.
- 137J. Shi, P. W. Kantoff, R. Wooster, O. C. Farokhzad, Nat. Rev. Cancer 2017, 17, 20–37.
- 138X. Zhang, X. Zhang, H. Guo, S. Jia, Y. Li, S. Xing, J. Chang, S. Wang, Adv. Healthcare Mater. 2023, 12, 2301469.
- 139X. Zhang, S. Wang, G. Cheng, P. Yu, J. Chang, Engineering 2022, 13, 18–30.
- 140G. Cheng, W. Zong, H. Guo, F. Li, X. Zhang, P. Yu, F. Ren, X. Zhang, X. Shi, F. Gao, J. Chang, S. Wang, Adv. Mater. 2021, 33, 2100398.
- 141S. Wang, P. Huang, X. Chen, Adv. Mater. 2016, 28, 7340–7364.
- 142Y. Chen, F. Liu, S. Pal, Q. Hu, Chem. Soc. Rev. 2024, 53, 9582–9608.
- 143F. Yang, Q. Luo, Y. Wang, H. Liang, Y. Wang, Z. Hou, C. Wan, Y. Wang, Z. Liu, Y. Ye, L. Zhu, J. Wu, F. Yin, Z. Li, J. Am. Chem. Soc. 2023, 145, 7879–7887.
- 144C. Ding, C. Chen, X. Zeng, H. Chen, Y. Zhao, ACS Nano 2022, 16, 13513–13553.
- 145Y. Zhang, H. Cui, R. Zhang, H. Zhang, W. Huang, Adv. Sci. 2021, 8, 2101454.
- 146S. Wang, G. Yu, Z. Wang, O. Jacobson, L.-S. Lin, W. Yang, H. Deng, Z. He, Y. Liu, Z.-Y. Chen, X. Chen, Angew. Chem. Int. Ed. 2019, 58, 14758–14763.
- 147H. Li, X. Zhang, S. Chen, C. Cao, X. Zhang, X. Li, S. Xing, S. Jia, J. Li, S. Wang, ACS Mater. Lett. 2024, 6, 2599–2608.
- 148X. Zhang, H. Guo, X. Zhang, X. Shi, P. Yu, S. Jia, C. Cao, S. Wang, J. Chang, Biomater. Sci. 2023, 11, 1066–1074.
- 149X. Zhang, X. Zhang, S. Chen, Y. Liu, C. Cao, G. Cheng, S. Wang, J. Colloid Interface Sci. 2024, 670, 279–287.
- 150X. Zhang, S. Wang, G. Cheng, P. Yu, J. Chang, X. Chen, Matter 2021, 4, 26–53.
- 151J. Huang, Z. Yao, B. Li, Y. Ping, J. Controlled Release 2023, 361, 270–279.
- 152J. Gao, L. Yang, S. Lei, F. Zhou, H. Nie, B. Peng, T. Xu, X. Chen, X. Yang, C. Sheng, Y. Rao, K. Pu, J. Jin, Z. Xu, H. Yu, Sci. Bull. 2023, 68, 1069–1085.
- 153M.-Y. Lv, D.-Y. Hou, S.-W. Liu, D.-B. Cheng, H. Wang, ACS Nano 2024, 19, 101–119.
- 154Z. Li, T. Jiang, X. Yuan, B. Li, C. Wu, Y. Li, Y. Huang, X. Xie, W. Pan, Y. Ping, J. Controlled Release 2024, 374, 441–453.
- 155W. Gao, X. Xia, X. Yang, Q. Li, X. Xia, W. Huang, D. Yan, Chem. Eng. J. 2024, 495, 153437.
- 156Y. Liu, H. Wang, M. Ding, W. Yao, K. Wang, I. Ullah, E. Bulatov, Y. Yuan, Nano Lett.. 2024, 24, 8741–8751.
- 157S. He, F. Gao, J. Ma, H. Ma, G. Dong, C. Sheng, Angew. Chem. Int. Ed. 2021, 60, 23299–23305.
- 158S. Zhang, Y. Lai, J. Pan, M. Saeed, S. Li, H. Zhou, X. Jiang, J. Gao, Y. Zhu, H. J. A. M. Yu, Adv. Mater. 2024, 2314132.
- 159J. Gao, X. Jiang, S. Lei, W. Cheng, Y. Lai, M. Li, L. Yang, P. Liu, X.-h. Chen, M. Huang, H. Yu, H. Xu, Z. Xu, Nat. Commun. 2024, 15, 6608.
- 160J. Choi, B. Park, J. Y. Park, D. Shin, S. Lee, H. Y. Yoon, K. Kim, S. H. Kim, Y. Kim, Y. Yang, M. K. Shim, Adv. Mater. 2024, 36, 2405475.
- 161W. Wang, C. Zhu, B. Zhang, Y. Feng, Y. Zhang, J. Li, J. Am. Chem. Soc. 2023, 145, 16642–16649.
- 162C. Yang, Y. Yang, Y. Li, Q. Ni, J. Li, J. Am. Chem. Soc. 2023, 145, 385–391.
- 163W. Cheng, S. Li, X. Wen, S. Han, S. Wang, H. Wei, Z. Song, Y. Wang, X. Tian, X. Zhang, Chem. Commun. 2021, 57, 12852–12855.
- 164H. Liu, C. Ren, R. Sun, H. Wang, Y. Zhan, X. Yang, B. Jiang, H. Chen, Chem. Commun. 2022, 58, 10072–10075.
- 165S. Wang, D. Luo, C. Pu, X. Ma, H. Zhang, Z. Feng, R. Deng, S. Yu, Y. Liu, Q. Huang, R. Li, Eur. J. Med. Chem. 2023, 248, 115082.
- 166R. Dutta, A. Devarajan, A. Talluri, R. Das, S. Thayumanavan, J. Am. Chem. Soc. 2025.
- 167M. Reynders, B. S. Matsuura, M. Berouti, D. Simoneschi, A. Marzio, M. Pagano, D. Trauner, Sci. Adv. 2020, 6, eaay5064.
- 168J. Cheng, J. Zhang, S. He, M. Li, G. Dong, C. Sheng, Angew. Chem. Int. Ed. 2024, 63, e202315997.
- 169Q. Zhang, C. S. Kounde, M. Mondal, J. L. Greenfield, J. R. Baker, S. Kotelnikov, M. Ignatov, C. P. Tinworth, L. Zhang, D. Conole, E. De Vita, D. Kozakov, A. McCluskey, J. D. Harling, M. J. Fuchter, E. W. Tate, Chem. Commun. 2022, 58, 10933–10936.
- 170M. Chang, F. Gao, D. Pontigon, G. Gnawali, H. Xu, W. Wang, J. Am. Chem. Soc. 2023, 145, 14155–14163.
- 171K. An, X. Deng, H. Chi, Y. Zhang, Y. Li, M. Cheng, Z. Ni, Z. Yang, C. Wang, J. Chen, J. Bai, C. Ran, Y. Wei, J. Li, P. Zhang, F. Xu, W. Tan, Angew. Chem. Int. Ed. 2023, 62, e202306824.
- 172S. He, Y. Fang, Y. Zhu, Z. Ma, G. Dong, C. Sheng, Adv. Sci. 2024, 11, 2401623.
- 173J. Gao, B. Hou, Q. Zhu, L. Yang, X. Jiang, Z. Zou, X. Li, T. Xu, M. Zheng, Y.-H. Chen, Z. Xu, H. Xu, H. Yu, Nat. Commun. 2022, 13, 4318.
- 174S. Shi, Y. Du, Y. Zou, J. Niu, Z. Cai, X. Wang, F. Qiu, Y. Ding, G. Yang, Y. Wu, Y. Xu, Q. Zhu, J. Med. Chem. 2022, 65, 5057–5071.
- 175H. Cho, S. I. Jeon, M. K. Shim, C.-H. Ahn, K. Kim, Biomaterials 2023, 295, 122038.
- 176C. Zhang, M. Xu, S. He, J. Huang, C. Xu, K. Pu, Adv. Mater. 2023, 35, 2208553.
- 177P. Zhu, Y. Chen, J. Shi, Adv. Mater. 2020, 32, 2001976.
- 178X. Lin, S. Liu, X. Zhang, R. Zhu, S. Chen, X. Chen, J. Song, H. Yang, Angew. Chem. Int. Ed. 2020, 59, 1682–1688.
- 179G. Xue, K. Wang, D. Zhou, H. Zhong, Z. Pan, J. Am. Chem. Soc. 2019, 141, 18370–18374.
- 180L. Wu, J. Huang, K. Pu, T. D. James, Nat. Rev. Chem. 2021, 5, 406–421.
- 181Y. Hu, J. Liu, M. Xu, K. Pu, J. Am. Chem. Soc. 2025, 147, 7148–7157.
- 182M. Chen, C. Wang, X. Wang, Z. Tu, Z. Ding, Z. Liu, Adv. Mater. 2024, 36, 2307818.
- 183P. Pfaff, K. T. G. Samarasinghe, C. Crews, E. Carreira, ACS Cent. Sci. 2019, 5, 1682–1690.
- 184J. Morstein, A. Amatuni, A. Shuster, W. Kuttenlochner, T. Ko, D. Abegg, M. Groll, A. Adibekian, H. Renata, D. H. Trauner, Angew. Chem. Int. Ed. 2024, 63, e202314791.
- 185T. Ko, C. Jou, A. B. Grau-Perales, M. Reynders, A. A. Fenton, D. Trauner, ACS Chem. Neurosci. 2023, 14, 3704–3713.
- 186M. Reynders, D. Trauner, Cell Chem. Biol. 2021, 28, 969–986.
- 187Y.-H. Jin, M.-C. Lu, Y. Wang, W.-X. Shan, X.-Y. Wang, Q.-D. You, Z.-Y. Jiang, J. Med. Chem. 2020, 63, 4644–4654.
- 188D. Thang Cong, J. W. Lau, C. Sun, S. Liu, K. T. Kha, S. T. Lim, Y. Y. Oon, Y. P. Kwan, J. J. Ma, Y. Mu, X. Liu, T. J. Carney, X. Wang, B. Xing, Sci. Adv. 2022, 8, eabq2216.
- 189C. Sun, S. Liu, J. W. Lau, H. Yang, Y. Chen, B. Xing, Angew. Chem. Int. Ed. 2025, e202423057.
- 190S. Xie, J. Zhu, Y. Peng, F. Zhan, F. Zhan, C. He, D. Feng, J. Xie, J. Liu, H. Zhu, H. Yao, J. Xu, Z. Su, S. Xu, Angew. Chem. Int. Ed. 2025, e202421713.
- 191J. Zhan, X. Li, Z. Feng, Z. Liu, Z. Feng, J.-J. Zhu, J. Zhang, Angew. Chem. Int. Ed. 2025, 64, e202415323.
- 192N. Chen, Z. Zhang, X. Liu, H. Wang, R.-C. Guo, H. Wang, B. Hu, Y. Shi, P. Zhang, Z. Liu, Z. Yu, J. Am. Chem. Soc. 2024, 146, 10753–10766.
- 193H. Lebraud, D. J. Wright, C. N. Johnson, T. D. Heightman, ACS Cent. Sci. 2016, 2, 927–934.
- 194M. d. M. Noblejas-Lopez, D. Tebar-Garcia, R. Lopez-Rosa, A. Alcaraz-Sanabria, P. Cristobal-Cueto, A. Pinedo-Serrano, L. Rivas-Garcia, E. M. Galan-Moya, Pharmaceutics 2023, 15, 2442.
- 195C. Wang, C. Zheng, H. Wang, L. Zhang, Z. Liu, P. Xu, Eur. J. Med. Chem. 2022, 235, 114290.
- 196Y. Zhao, D. Song, Z. Wang, Q. Huang, F. Huang, Z. Ye, D. Wich, M. Chen, J. Khirallah, S. Gao, Y. Liu, Q. Xu, Nat. Biomed. Eng. 2024, 9, 234–248.
- 197Y. Chen, S. Pal, W. Li, F. Liu, S. Yuan, Q. Hu, Nat. Biotechnol. 2024.
- 198X. Teng, X. Zhao, Y. Dai, X. Zhang, Q. Zhang, Y. Wu, D. Hu, J. Li, J. Am. Chem. Soc. 2024, 146, 27382–27391.
