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However, complex tumor microenvironments and the performance limitations of traditional liposomes restrict clinical translation. Hyaluronic acid (HA)-modified nanoliposomes effectively target CD44-overexpressing tumor cells. Combination therapy enhances treatment efficacy and delays drug resistance. Here, we developed paclitaxel (PTX) liposomes co-modified with ginsenoside compound K (CK) and HA using film dispersion. Compared to cholesterol (Ch), CK substantially improved encapsulation efficiency and stability. In vitro release studies revealed pH-responsive behavior, with slower release at pH 7.4 versus faster release at pH 5. In vitro cytotoxicity assays demonstrated that replacing Ch with CK in modified liposomes considerably decreased HCT-116 cell viability. Furthermore, flow cytometry and fluorescence microscopy showed a higher cellular uptake of PTX-CK-Lip-HA in CD44-high cells, reflected in the lower half maximal inhibitory concentrations. Overall, CK\/HA-modified liposomes represent an innovative, targeted delivery system for enhanced tumor therapy via pH-triggered drug release and CD44 binding.<\/jats:p>","DOI":"10.3390\/polym16030405","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T09:04:21Z","timestamp":1706778261000},"page":"405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Multifunctional Liposomes Co-Modified with Ginsenoside Compound K and Hyaluronic Acid for Tumor-Targeted Therapy"],"prefix":"10.3390","volume":"16","author":[{"given":"Xiaoyan","family":"You","sequence":"first","affiliation":[{"name":"College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471023, China"},{"name":"Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471023, China"},{"name":"Haihe Laboratory of Synthetic Biology, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5469-5413","authenticated-orcid":false,"given":"Yue","family":"Chen","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoping","family":"Zhao","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China"},{"name":"Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1136\/gutjnl-2015-310912","article-title":"Global patterns and trends in colorectal cancer incidence and mortality","volume":"66","author":"Arnold","year":"2017","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cardoso, R.V., Pereira, P.R., Freitas, C.S., and Paschoalin, V.M.F. 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