{ "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.", "abstract_shown": true, "affiliations": [ "Department 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.", "Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China.", "Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, China.", "Cancer Center of Zhejiang University, Hangzhou, China.", "Department 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. xinyizhou@zju.edu.cn.", "Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China. xinyizhou@zju.edu.cn.", "Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, China. xinyizhou@zju.edu.cn.", "Cancer Center of Zhejiang University, Hangzhou, China. xinyizhou@zju.edu.cn.", "Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.", "Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.", "Department 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. qxiao3@zju.edu.cn.", "Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China. qxiao3@zju.edu.cn.", "Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, China. qxiao3@zju.edu.cn.", "Cancer Center of Zhejiang University, Hangzhou, China. qxiao3@zju.edu.cn.", "Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. quanzhou91@zju.edu.cn.", "Department 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. dingkefeng@zju.edu.cn.", "Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China. dingkefeng@zju.edu.cn.", "Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, China. dingkefeng@zju.edu.cn.", "Cancer Center of Zhejiang University, Hangzhou, China. dingkefeng@zju.edu.cn." ], "article_type": "research support, non u.s. gov't", "arxiv": null, "author_total": 11, "authors": [ { "affs": [ 0, 1, 2, 3 ], "name": "Hang Yang", "orcid": "0000-0003-1803-4877" }, { "affs": [ 4, 5, 6, 7 ], "name": "Xinyi Zhou" }, { "affs": [ 8 ], "name": "Jiafeng Wang", "orcid": "0009-0006-8114-6061" }, { "affs": [ 0 ], "name": "Chenyue Yang" }, { "affs": [ 0 ], "name": "Yuzhao Jin" }, { "affs": [ 0 ], "name": "Xufeng Liao" }, { "affs": [ 1, 9 ], "name": "Xiangrui Liu", "orcid": "0000-0003-4960-5847" }, { "affs": [ 0, 1, 2, 3 ], "name": "Chuansheng Guo" }, { "affs": [ 10, 11, 12, 13 ], "name": "Qian Xiao", "orcid": "0000-0002-0120-2371" }, { "affs": [ 14 ], "name": "Quan Zhou", "orcid": "0000-0002-6252-0154" }, { "affs": [ 15, 16, 17, 18 ], "name": "Kefeng Ding", "orcid": "0000-0002-2380-3717" } ], "bibtex": "https://research.draconitic.com/paper/cs5hga39x8s22.bib", "cited_by": 0, "doi": "10.1038/s41467-026-77697-5", "fulltext_url": "https://europepmc.org/articles/PMC13677754", "id": "cs5hga39x8s22", "issns": [ "2041-1723" ], "landing_url": "https://europepmc.org/article/MED/42893987", "language": "eng", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|Protein Degradation and Inhibitors" ] ], "openalex": "W7213471593", "pdf_url": "https://europepmc.org/articles/PMC13677754?pdf=render", "pmcid": "PMC13677754", "pmid": "42893987", "published": "2026-09-17", "publisher": null, "ris": "https://research.draconitic.com/paper/cs5hga39x8s22.ris", "sources": [ { "first_seen": "2026-10-30T12:19:41Z", "native_id": "MED:42893987", "source": "europepmc", "url": "https://europepmc.org/article/MED/42893987" } ], "subjects": [ { "field": "biochemistry", "origin": "openalex:1312|Protein Degradation and Inhibitors", "subfield": "molecular-biology" } ], "title": "A lipoprotein-biomimetic nanoplatform for oncogenic KRAS mutation-specific lysosome-targeting protein degradation.", "title_text": "A lipoprotein-biomimetic nanoplatform for oncogenic KRAS mutation-specific lysosome-targeting protein degradation.", "type": "peer-reviewed", "updated_at": "2026-10-30T12:19:41Z", "url": "https://research.draconitic.com/paper/cs5hga39x8s22", "venue": "Nature communications", "versions": [] }