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Peer-reviewedCC BY-NC-NDNature communications

A lipoprotein-biomimetic nanoplatform for oncogenic KRAS mutation-specific lysosome-targeting protein degradation.

  • Hang Yang1,2,3,4
  • Xinyi Zhou5,6,7,8
  • Jiafeng Wang9
  • Chenyue Yang1
  • Yuzhao Jin1
  • Xufeng Liao1
  • Xiangrui Liu2,10
  • Chuansheng Guo1,2,3,4
  • Qian Xiao11,12,13,14
  • Quan Zhou15
  • Kefeng Ding16,17,18,19
19 affiliations
  1. 1Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  2. 2Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China.
  3. 3Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, China.
  4. 4Cancer Center of Zhejiang University, Hangzhou, China.
  5. 5Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  6. 6Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China. [email protected].
  7. 7Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, China. [email protected].
  8. 8Cancer Center of Zhejiang University, Hangzhou, China. [email protected].
  9. 9Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
  10. 10Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.
  11. 11Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  12. 12Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China. [email protected].
  13. 13Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, China. [email protected].
  14. 14Cancer Center of Zhejiang University, Hangzhou, China. [email protected].
  15. 15Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  16. 16Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  17. 17Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China. [email protected].
  18. 18Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, China. [email protected].
  19. 19Cancer Center of Zhejiang University, Hangzhou, China. [email protected].
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Abstract

Lysosome-targeting protein degradation strategies have evolved to leverage lineage-specific receptors to improve selectivity, yet remain unable to distinguish malignant from normal cells within the same lineage. Since oncogenic mutations are the defining feature of malignant cells, we here develop KRAS-mutated (MT) tumor targeting chimeras (KRASTAC), a lipoprotein-biomimetic nanoplatform that hijacks the enhanced macropinocytosis in KRAS-MT cells for mutation-specific protein degradation. KRASTAC potently degrades diverse proteins including epidermal growth factor receptor and programmed cell death ligand 1 (PD-L1) in KRAS-MT cells at a low antibody concentration of 2.5 nM within 9 h, with minimal impact in KRAS wild-type (WT) cells. Furthermore, KRASTAC exhibits mutation-specific tumor accumulation and protein degradation in vivo. KRASTAC-induced PD-L1 degradation leads to robust antitumor efficacy and reprogramming of the immunosuppressive microenvironment in mice carrying Kras-MT tumors. Our work presents KRASTAC as a potent mutation-specific protein degradation strategy for KRAS-MT cancers and establishes macropinocytosis as a route for lysosome-targeting protein degradation.

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Cite

BibTeXRIS
BibTeX
@article{yang2026lipoproteinbiomimetic,
  title = {{A lipoprotein-biomimetic nanoplatform for oncogenic KRAS mutation-specific lysosome-targeting protein degradation.}},
  author = {Hang Yang and Xinyi Zhou and Jiafeng Wang and Chenyue Yang and Yuzhao Jin and Xufeng Liao and Xiangrui Liu and Chuansheng Guo and Qian Xiao and Quan Zhou and Kefeng Ding},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77697-5},
  url = {https://europepmc.org/article/MED/42893987},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - A lipoprotein-biomimetic nanoplatform for oncogenic KRAS mutation-specific lysosome-targeting protein degradation.
AU  - Hang Yang
AU  - Xinyi Zhou
AU  - Jiafeng Wang
AU  - Chenyue Yang
AU  - Yuzhao Jin
AU  - Xufeng Liao
AU  - Xiangrui Liu
AU  - Chuansheng Guo
AU  - Qian Xiao
AU  - Quan Zhou
AU  - Kefeng Ding
PY  - 2026
DA  - 2026/09/17
JO  - Nature communications
DO  - 10.1038/s41467-026-77697-5
UR  - https://europepmc.org/article/MED/42893987
AB  - Lysosome-targeting protein degradation strategies have evolved to leverage lineage-specific receptors to improve selectivity, yet remain unable to distinguish malignant from normal cells within the same lineage. Since oncogenic mutations are the defining feature of malignant cells, we here develop KRAS-mutated (MT) tumor targeting chimeras (KRASTAC), a lipoprotein-biomimetic nanoplatform that hijacks the enhanced macropinocytosis in KRAS-MT cells for mutation-specific protein degradation. KRASTAC potently degrades diverse proteins including epidermal growth factor receptor and programmed cell death ligand 1 (PD-L1) in KRAS-MT cells at a low antibody concentration of 2.5 nM within 9 h, with minimal impact in KRAS wild-type (WT) cells. Furthermore, KRASTAC exhibits mutation-specific tumor accumulation and protein degradation in vivo. KRASTAC-induced PD-L1 degradation leads to robust antitumor efficacy and reprogramming of the immunosuppressive microenvironment in mice carrying Kras-MT tumors. Our work presents KRASTAC as a potent mutation-specific protein degradation strategy for KRAS-MT cancers and establishes macropinocytosis as a route for lysosome-targeting protein degradation.
SN  - 2041-1723
ER  -