State Key Lab of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200230, P. R. China.
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200230, P. R. China.
Small. 2024 Jul;20(30):e2308335. doi: 10.1002/smll.202308335. Epub 2024 Feb 29.
Tumor-derived exosomes (TDEs) induced extracellular microenvironment has recently been validated to be critical for tumor progression and metastasis, however, remodeling it for oncotherapy still remains a major challenge due to difficulty in regulation of TDEs secretion. Herein, the supramolecular chiral nanofibers, composed of -phenylalanine derivates (L/D-Phe) and linear hyaluronic acid (HA), are successfully employed to construct TDEs induced anti-tumor extracellular microenvironment. The left-handed L-Phe @HA nanofibers significantly inhibit TDEs secretion into extracellular microenvironment, which results in suppression of tumor proliferation and metastasis in vitro and vivo. Biological assays and theoretical modeling reveal that these results are mainly attributed to strong adsorption of the key exosomes transporters (Ras-related protein Rab-27A and synaptosome-associated protein 23) on left-handed L-Phe @HA nanofibers via enhanced stereoselective interaction, leading to degradation and phosphorylated dropping of exosomes transporters. Subsequently, transfer function of exosomes transporters is limited, which causes remarkable inhibition of TDEs secretion. These findings provide a promising novel insight of chiral functional materials to establish an anti-tumor extracellular microenvironment via regulation of TDEs secretion.
肿瘤衍生的外泌体（TDEs）诱导的细胞外微环境最近被证实对肿瘤的进展和转移至关重要，然而，由于难以调节 TDEs 的分泌，将其重塑用于肿瘤治疗仍然是一个主要挑战。在此，由 - 苯丙氨酸衍生物（L/D-Phe）和线性透明质酸（HA）组成的超分子手性纳米纤维成功地用于构建 TDEs 诱导的抗肿瘤细胞外微环境。左手性 L-Phe@HA 纳米纤维显著抑制 TDEs 分泌到细胞外微环境中，从而抑制体外和体内肿瘤的增殖和转移。生物测定和理论建模表明，这些结果主要归因于关键外泌体转运蛋白（Ras 相关蛋白 Rab-27A 和突触相关蛋白 23）在手性 L-Phe@HA 纳米纤维上通过增强立体选择性相互作用的强烈吸附，导致外泌体转运蛋白的降解和磷酸化下降。随后，外泌体转运蛋白的传递功能受到限制，导致 TDEs 分泌的显著抑制。这些发现为手性功能材料提供了一个有前途的新视角，通过调节 TDEs 的分泌来建立抗肿瘤细胞外微环境。
