TARGETED DEGRADATION OF EXTRACELLULAR PROTEINS: EMERGING STRATEGIES AND THERAPEUTIC POTENTIAL
DOI:
https://doi.org/10.65327/hsn.v10i3.2486Keywords:
Extracellular protein degradation, LYTACs, Lysosomal degradation, Targeted protein degradation, Therapeutic targetingAbstract
Extracellular protein degradation by targeted degradation approaches is an area that is growing in significance as an extension of the existing methods of targeted protein degradation to enable selective degradation of extracellular disease targets that are inaccessible through proteasome-mediated protein degradation approaches. The purpose of this review was to assess the biology of extracellular protein degradation, platforms of degradation, therapeutic use cases, translational benefits, existing limitations, and current trends in the field of extracellular protein degradation. A thorough literature review was conducted on different aspects of extracellular protein degradation including lysosome targeting chimeras, antibody degrader technology, cytokine receptor targeting chimeras, small molecule technology, and extracellular vesicles. The presented evidence clearly indicates that internalization via receptors and lysosomal targeting constitute the core mechanism of extracellular protein degradation. LYTACs have been established as the most well-characterized system, although novel approaches such as macromolecules, small molecules, and vesicles may offer more flexibility in terms of targets and delivery. Possible uses may be for the treatment of cancer, inflammation, neurodegenerative diseases, among others where extracellular protein-mediated pathology occurs. Limitations include issues regarding the presence of the required receptor, biodistribution, pharmacokinetics, immunogenicity, off-target degradation, difficulty in manufacturing, and insufficient clinical evidence.
References
Anwar, S., Alrumaihi, F., Sarwar, T., Babiker, A. Y., Khan, A. A., Prabhu, S. V., & Rahmani, A. H. (2024). Exploring therapeutic potential of catalase: Strategies in disease prevention and management. Biomolecules, 14(6), 697.
Banik, S. M., Pedram, K., Wisnovsky, S., Ahn, G., Riley, N. M., & Bertozzi, C. R. (2020). Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature, 584(7820), 291-297.
Buddhiraju, H. S., Yadav, D. N., Dey, S., Eswar, K., Padmakumar, A., & Rengan, A. K. (2024). Advances in peptide-decorated targeted drug delivery: exploring therapeutic potential and nanocarrier strategies. ACS Applied Bio Materials, 7(8), 4879-4893.
Caianiello, D. F., Zhang, M., Ray, J. D., Howell, R. A., Swartzel, J. C., Branham, E. M., ... & Spiegel, D. A. (2021). Bifunctional small molecules that mediate the degradation of extracellular proteins. Nature chemical biology, 17(9), 947-953.
Cassidy, K., & Zhao, H. (2023). Redefining the scope of targeted protein degradation: translational opportunities in hijacking the autophagy–lysosome pathway. Biochemistry, 62(3), 580-587.
Chen, R., Zou, J., Chen, J., Zhong, X., Kang, R., & Tang, D. (2025). Pattern recognition receptors: function, regulation and therapeutic potential. Signal Transduction and Targeted Therapy, 10(1), 216.
Chen, X., Zhou, Y., Zhao, Y., & Tang, W. (2023). Targeted degradation of extracellular secreted and membrane proteins. Trends in pharmacological sciences, 44(11), 762-775.
Chirnomas, D., Hornberger, K. R., & Crews, C. M. (2023). Protein degraders enter the clinic—a new approach to cancer therapy. Nature reviews Clinical oncology, 20(4), 265-278.
Crisman, E., Duarte, P., Dauden, E., Cuadrado, A., Rodríguez‐Franco, M. I., López, M. G., & León, R. (2023). KEAP1‐NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential. Medicinal research reviews, 43(1), 237-287.
Dale, B., Cheng, M., Park, K. S., Kaniskan, H. Ü., Xiong, Y., & Jin, J. (2021). Advancing targeted protein degradation for cancer therapy. Nature Reviews Cancer, 21(10), 638-654.
Ding, Y., Fei, Y., & Lu, B. (2020). Emerging new concepts of degrader technologies. Trends in Pharmacological Sciences, 41(7), 464-474.
Giordano, L., Porta, G. D., Peretti, G. M., & Maffulli, N. (2020). Therapeutic potential of microRNA in tendon injuries. British medical bulletin, 133(1), 79-94.
Hadian, K., & Stockwell, B. R. (2023). The therapeutic potential of targeting regulated non-apoptotic cell death. Nature Reviews Drug Discovery, 22(9), 723-742.
Han, D., Li, Z., Wang, F., Cheng, K., & Shen, D. (2024). Apoptotic extracellular vesicles: mechanisms, applications, and therapeutic potential. Med-X, 2(1), 27.
Hinterndorfer, M., Spiteri, V. A., Ciulli, A., & Winter, G. E. (2025). Targeted protein degradation for cancer therapy. Nature Reviews Cancer, 25(7), 493-516.
Huang, J., Zhang, L., Wan, D., Zhou, L., Zheng, S., Lin, S., & Qiao, Y. (2021). Extracellular matrix and its therapeutic potential for cancer treatment. Signal transduction and targeted therapy, 6(1), 153.
Jiang, Y., Geng, M., & Bai, L. (2020). Targeting biofilms therapy: Current research strategies and development hurdles. Microorganisms, 8(8), 1222.
Kumar, M. A., Baba, S. K., Sadida, H. Q., Marzooqi, S. A., Jerobin, J., Altemani, F. H., ... & Bhat, A. A. (2024). Extracellular vesicles as tools and targets in therapy for diseases. Signal transduction and targeted therapy, 9(1), 27.
Li, Y. Y., Yang, Y., Zhang, R. S., Ge, R. X., & Xie, S. B. (2025). Targeted degradation of membrane and extracellular proteins with LYTACs. Acta Pharmacologica Sinica, 46(1), 1-7.
Lin, J., Jin, J., Shen, Y., Zhang, L., Gong, G., Bian, H., ... & Luan, X. (2021). Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins. Theranostics, 11(17), 8337.
Lin, Z., Wu, Y., Xu, Y., Li, G., Li, Z., & Liu, T. (2022). Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential. Molecular cancer, 21(1), 179.
Mamun, M. A. A., Bakunts, A. G., & Chernorudskiy, A. L. (2025). Targeted degradation of extracellular proteins: state of the art and diversity of degrader designs. Journal of hematology & oncology, 18(1), 52.
Pance, K., Gramespacher, J. A., Byrnes, J. R., Salangsang, F., Serrano, J. A. C., Cotton, A. D., ... & Wells, J. A. (2023). Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nature biotechnology, 41(2), 273-281.
Paudel, R. R., Lu, D., Roy Chowdhury, S., Monroy, E. Y., & Wang, J. (2023). Targeted protein degradation via lysosomes. Biochemistry, 62(3), 564-579.
Samarasinghe, K. T., & Crews, C. M. (2021). Targeted protein degradation: A promise for undruggable proteins. Cell chemical biology, 28(7), 934-951.
Soares Martins, T., Trindade, D., Vaz, M., Campelo, I., Almeida, M., Trigo, G., ... & Henriques, A. G. (2021). Diagnostic and therapeutic potential of exosomes in Alzheimer’s disease. Journal of Neurochemistry, 156(2), 162-181.
Sun, H., Li, N., & Cai, X. (2025). Development of Antibody‐Based Strategies for Targeted Degradation of Membrane and Extracellular Proteins. ChemBioChem, 26(16), e202500184.
Sung, J., Seo, Y., & Lee, J. Y. (2026). From undruggable to degradable: Strategic expansion of targeted protein degradation in cancer therapy. Molecular Therapy.
Tong, B., Zhang, X., Zhu, D., Wang, Y., Wei, J., Ou, Z., ... & Yang, C. (2026). Extracellular vesicle-based targeted protein degradation platform for multiple extracellular proteins. EMBO Molecular Medicine, 18(2), 759-794.
Tsai, J. M., Nowak, R. P., Ebert, B. L., & Fischer, E. S. (2024). Targeted protein degradation: from mechanisms to clinic. Nature Reviews Molecular Cell Biology, 25(9), 740-757.
Wells, J. A., & Kumru, K. (2024). Extracellular targeted protein degradation: an emerging modality for drug discovery. Nature Reviews Drug Discovery, 23(2), 126-140.
Xiao, Y. L., Gong, Y., Qi, Y. J., Shao, Z. M., & Jiang, Y. Z. (2024). Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential. Signal Transduction and Targeted Therapy, 9(1), 59.
Yang, X., Gao, X., Jiang, X., Yue, K., & Luo, P. (2024). Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases. Neural Regeneration Research, 20(11), 3076.
Zhang, M., & Zhang, B. (2025). Extracellular matrix stiffness: mechanisms in tumor progression and therapeutic potential in cancer. Experimental hematology & oncology, 14(1), 54.
Zhao, L., Zhao, J., Zhong, K., Tong, A., & Jia, D. (2022). Targeted protein degradation: mechanisms, strategies and application. Signal transduction and targeted therapy, 7(1), 113.
Zhong, G., Chang, X., Xie, W., & Zhou, X. (2024). Targeted protein degradation: advances in drug discovery and clinical practice. Signal transduction and targeted therapy, 9(1), 308.
Zhou, B., Chen, Q., Zhang, Q., Tian, W., Chen, T., & Liu, Z. (2024). Therapeutic potential of adipose-derived stem cell extracellular vesicles: from inflammation regulation to tissue repair. Stem cell research & therapy, 15(1), 249.
Zhu, R., Zhang, H., & Chen, P. R. (2025). Targeted protein degradation in the transmembrane and extracellular space. Science, 390(6776), eadx5094.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 International Journal For Research In Health Sciences And Nursing
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
In consideration of the journal, Green Publication taking action in reviewing and editing our manuscript, the authors undersigned hereby transfer, assign, or otherwise convey all copyright ownership to the Editorial Office of the Green Publication in the event that such work is published in the journal. Such conveyance covers any product that may derive from the published journal, whether print or electronic. Green Publication shall have the right to register copyright to the Article in its name as claimant, whether separately
or as part of the journal issue or other medium in which the Article is included.
By signing this Agreement, the author(s), and in the case of a Work Made For Hire, the employer, jointly and severally represent and warrant that the Article is original with the author(s) and does not infringe any copyright or violate any other right of any third parties, and that the Article has not been published elsewhere, and is not being considered for publication elsewhere in any form, except as provided herein. Each author’s signature should appear below. The signing author(s) (and, in
