Lee Eunhee, Dang Loi Nguyen, Choi Jinsol, Kim Haesoo, Bastatas Lyndon, Park Soyeun
Department of Pharmacy, Keimyung University, 1095 Dalgubeoldaero Dalseo-gu, Daegu, 42601, Republic of Korea.
Premier Research Institute of Science and Mathematics, Department of Physics, Mindanao State University, Iligan Institute of Technology, Andres Bonifacio Ave, Tibanga, Iligan City, Lanao del Norte, 9200, Philippines.
Adv Sci (Weinh). 2025 Jul;12(26):e2502073. doi: 10.1002/advs.202502073. Epub 2025 Mar 27.
The mechanical elasticity of lipid nanoparticles (LNPs) is crucial to their pharmaceutical performance. This study investigates how the mechanical interactions between LNPs, target cells, and macrophages affect the internalization of LNPs into target cells at tumor sites. According to our bio-mechanical study, drug-resistant breast cancer cells are stiffer than sensitive ones, while invasive cells are softer; similarly, protumoral M2 macrophages are softer than M1 macrophages. Softer LNPs show increased cellular uptake in breast cancer cells and macrophages, with enhanced engulfment in invasive cells and M2 macrophages. Additionally, the presence of M2 macrophages promotes greater LNP internalization by cancer cells, facilitating the malignant and invasive nature of cancer cells. In addition, because breast cancer cells engulf LNPs via an energy-efficient fusion pathway but LNPs in macrophages undergo clathrin-mediated endocytosis, LNPs are internalized more into cancer cells but not into M2. In orthotopic tumor models, softer LNPs penetrate tumors quickly, enhancing suppression, whereas stiffer LNPs permeate slowly but show prolonged retention in stiffer tumors, supporting antitumor efficacy with repeated dosing. These findings underscore the importance of mechanical interactions between LNPs, target cells, and macrophages in optimizing LNP delivery systems, offering insights for more effective designs.
脂质纳米颗粒（LNPs）的机械弹性对其药物性能至关重要。本研究调查了LNPs、靶细胞和巨噬细胞之间的机械相互作用如何影响LNPs在肿瘤部位进入靶细胞的内化过程。根据我们的生物力学研究，耐药乳腺癌细胞比敏感细胞更硬，而侵袭性细胞更软；同样，促肿瘤的M2巨噬细胞比M1巨噬细胞更软。较软的LNPs在乳腺癌细胞和巨噬细胞中的细胞摄取增加，在侵袭性细胞和M2巨噬细胞中的吞噬作用增强。此外，M2巨噬细胞的存在促进癌细胞对LNP的更大内化，促进癌细胞的恶性和侵袭性。此外，由于乳腺癌细胞通过节能融合途径吞噬LNPs，但巨噬细胞中的LNPs经历网格蛋白介导的内吞作用，LNPs更多地内化到癌细胞中，而不是M2细胞中。在原位肿瘤模型中，较软的LNPs能快速穿透肿瘤，增强抑制作用，而较硬的LNPs渗透缓慢，但在较硬的肿瘤中显示出更长的滞留时间，支持重复给药的抗肿瘤疗效。这些发现强调了LNPs、靶细胞和巨噬细胞之间的机械相互作用在优化LNP递送系统中的重要性，为更有效的设计提供了见解。
