Zou Qingqing, Du Bin, Wang Xin, Wang Hongqiang, Sun Jiayu, Yang Xiaohai, Wang Kemin, Wang Qing
State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha 410082, PR China.
State Key Laboratory of Chemo and Biosensing, College of Chemistry and Chemical Engineering, Key Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan Province, Hunan University, Changsha 410082, PR China.
J Control Release. 2025 Jun 10;382:113701. doi: 10.1016/j.jconrel.2025.113701. Epub 2025 Apr 4.
Cell receptors are key regulators of cellular signaling. However, on-demand reversible engineering of cell receptors to intervene in cellular behavior remains a challenge. Herein, a reversible receptor engineer strategy (SL1/NCDP/Ada) was developed. Initially, ferrocene (Fc)-modified aptamer (SL1-Fc) engaged in biorecognition with the mesenchymal epidermal transition factor (Met) receptor. Subsequently, β-cyclodextrin polymers (β-CDPs) recognized SL1-Fc through host-guest interactions, spatially engineering the Met receptor and, consequently, influencing cell proliferation and migration behavior (SL1/CDP strategy). In addition, due to the stronger host-guest recognition of adamantane (Ada) and β-CD, Ada could compete with SL1-Fc to bind CDPs, causing CDPs to be released from the cell surface, thereby eliminating the regulatory effect of SL1/CDPs and achieving reversible regulation of cell migration behavior. This approach employed cross-networked (NCDP) and linear cyclodextrin polymers (LCDP). The results showed that SL1/NCDP could induce Met receptor aggregation and activated the Met receptor due to the compact network structure of NCDP. In contrast, SL1/LCDP could not induce Met receptor aggregation due to the large spatial spacing of monomers in LCDP. However, SL1/LCDP could significantly inhibit ligand hepatocyte growth factor (HGF)-induced Met receptor activation by targeting the Met receptor and indirectly regulate cell proliferation and migration behavior. This work provides a novel strategy to reversibly engineer cell receptors in a customized manner to regulate cell proliferation and migration behavior on demand.
细胞受体是细胞信号传导的关键调节因子。然而，对细胞受体进行按需可逆工程以干预细胞行为仍然是一个挑战。在此，开发了一种可逆受体工程策略（SL1/NCDP/Ada）。最初，二茂铁（Fc）修饰的适配体（SL1-Fc）与间充质表皮转化因子（Met）受体进行生物识别。随后，β-环糊精聚合物（β-CDPs）通过主客体相互作用识别SL1-Fc，对Met受体进行空间工程改造，从而影响细胞增殖和迁移行为（SL1/CDP策略）。此外，由于金刚烷（Ada）与β-环糊精具有更强的主客体识别能力，Ada可以与SL1-Fc竞争结合CDPs，使CDPs从细胞表面释放，从而消除SL1/CDPs的调节作用，实现对细胞迁移行为的可逆调节。该方法采用了交联网络（NCDP）和线性环糊精聚合物（LCDP）。结果表明，由于NCDP的紧密网络结构，SL1/NCDP可以诱导Met受体聚集并激活Met受体。相比之下，由于LCDP中单体的空间间距较大，SL1/LCDP不能诱导Met受体聚集。然而，SL1/LCDP可以通过靶向Met受体显著抑制配体肝细胞生长因子（HGF）诱导的Met受体激活，并间接调节细胞增殖和迁移行为。这项工作提供了一种新颖的策略，以定制的方式对细胞受体进行可逆工程，从而按需调节细胞增殖和迁移行为。
