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tools for delivering various substances into cells by crossing biological membranes. However, the effects of cell-penetrating peptide fusion proteins on the biological activity of antibodies remain to be fully understood. Here, we engineered a recombinant protein, LP-scFv, which combines the single-chain variable region of anti-human epidermal growth factor receptor-2 with a novel and non-oxic cell-penetrating peptide as a leader peptide. The introduction of this leader peptide led to a more than twofold increase in the internalization efficiency of the single-chain antibody, as confirmed using microscopic analysis and flow cytometry. The effects of the single-chain antibodies and LP-scFv on cell viability were evaluated using the MTT assay. Both the single-chain antibodies and LP-scFv reduced the viability of BT474 and NCI-N87 cells in a dose-dependent manner while exhibiting minimal toxicity towards MCF-7 and MCF-10A cells. Further investigation into LP-scFv\u2019s mechanism revealed that the induced leader peptide does not alter the MAPK-ERK1\/2 and PI3K\/AKT pathways of single-chain antibodies. An enhanced antitumor activity was also confirmed in an NCI-N87 tumor xenograft model in mice with a reduction of 45.2% in tumor growth inhibition (vs. 23.1% for scFv) with a 50 mg\/kg dose after orthotopic injection administration, which was equivalent to that of trastuzumab (vs. 55.7% for trastuzumab). Overall, these results indicate that LP-scFv exhibits significant permeation activity in HER2-positive cells to enhance the intracellular dose effect on antitumor activity in vitro and in vivo. This research lays the foundation for designing novel antibody-based therapies for cancer.<\/jats:p>","DOI":"10.3390\/molecules29061247","type":"journal-article","created":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T03:55:34Z","timestamp":1710215734000},"page":"1247","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Cell-Penetrating Peptide Improves Anti-HER2 Single-Chain Variable Fragment Internalization and Antitumor Activity against HER2-Positive Breast Cancer In Vitro and In Vivo"],"prefix":"10.3390","volume":"29","author":[{"given":"Junmin","family":"Li","sequence":"first","affiliation":[{"name":"MOE International Joint Laboratory for Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China"},{"name":"School of Biology and Food Science, Shangqiu Normal University, Shangqiu 476000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanting","family":"Zhou","sequence":"additional","affiliation":[{"name":"MOE International Joint Laboratory for Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuowei","family":"Su","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[{"name":"MOE International Joint Laboratory for Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China"},{"name":"Nanyang Medical College, Nanyang 473001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0837-730X","authenticated-orcid":false,"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"MOE International Joint Laboratory for Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China"},{"name":"NMPA Key Laboratory for Quality Control of Blood Products, Guangdong Institute for Drug Control, Guangzhou 510663, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Li","sequence":"additional","affiliation":[{"name":"MOE International Joint Laboratory for Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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