Reversible engineering of cell membrane receptors based on host-guest recognition for on-demand regulation of cellular behavior.

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.