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Methods: This study integrated COSMO-RS calculations, molecular dynamics simulations, and in vitro assays to systematically investigate the effects of lipid composition, drug modification, particle size, and solvent environment on dual-drug loading. Results: This work indicate that DMPS lipid membranes featuring highly polar headgroups and ordered bilayer structures stably bind both ICG and PTX, achieving drug-loading efficiencies (DLEs) of 7.2% and 5.6%, respectively. Carboxylation of PTX enhanced hydrogen bonding with DMPS, while alkyl chain modifications improved membrane insertion, though excessive chain length (e.g., C12) reduced stability due to increased flexibility. Increasing the LNP size from 50 nm to 250 nm raised the DLE of PTX from 4.7% to 8.1%, while sizes beyond 500 nm led to membrane destabilization. The use of 20 vol% ethanol increased total drug loading by 51% by disrupting the hydration shell of ICG and suppressing PTX aggregation; however, ethanol concentrations exceeding 40 vol% intensified drug\u2013solvent competition and weakened membrane binding. Conclusions: This study provides a comprehensive elucidation of the multifactorial regulatory mechanisms underlying dual-drug loading in LNPs, offering a theoretical basis for the rational design of efficient co-delivery systems.<\/jats:p>","DOI":"10.3390\/pharmaceutics18040505","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:37:42Z","timestamp":1776677862000},"page":"505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Study on the Mechanisms and Key Influencing Factors of Paclitaxel and Indocyanine Green Co-Loading in Lipid Nanoparticles"],"prefix":"10.3390","volume":"18","author":[{"given":"Weishen","family":"Zhong","sequence":"first","affiliation":[{"name":"School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0457-3415","authenticated-orcid":false,"given":"Kai","family":"Yue","sequence":"additional","affiliation":[{"name":"School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China"},{"name":"Shunde Graduate School, University of Science and Technology Beijing, Shunde District, Foshan 528399, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genpei","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyang","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China"},{"name":"Shunde Graduate School, University of Science and Technology Beijing, Shunde District, Foshan 528399, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.canlet.2019.04.017","article-title":"Emerging strategies in cancer therapy combining chemotherapy with immunotherapy","volume":"454","author":"Luo","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_2","first-page":"86","article-title":"Breaking malignant nuclei as a non-mitotic mechanism of taxol\/paclitaxel","volume":"2","author":"Smith","year":"2021","journal-title":"J. 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