Receptor Dimerization-Engineering Hydrogel to On-Demand Regulate Cellular Behaviors

Manipulation of cell-surface receptor dimerization plays a critical role in modulating cellular behaviors, yet the controllable regulation and dimerization efficiency of receptors remain challenging. Here, a dynamic bispecific aptamer within triglycerol monostearate (TGMS) nanoparticles hydrogel termed REMEDY (receptor dimerization-engineering directed hydrogel) was developed to modulate cellular behavior in an on-demand manner. The REMEDY was fabricated by dual rolling circle amplification to deliver bispecific receptor tyrosine kinase (RTK) aptamers, thereby effectively promoting cell receptor dimerization. The TGMS nanoparticles loaded with restriction endonuclease EcoR I controllably released bispecific RTK aptamers through EcoR I-triggered hydrogel disintegration in response to inflammation. The REMEDY successfully manipulated cell-surface MET receptor dimerization and activated MAPK/ERK and PI3K/AKT signaling pathways. RNA sequencing analysis further revealed that activated pathways upregulated the expression of Krt1, Vegfb, while downregulating Il1b, which were closely associated with target cells proliferation, migration, and phenotypic polarization. A murine wound model was subsequently constructed to validate the practical therapeutic efficacy. Results demonstrated that REMEDY significantly enhanced wound healing rates by 26.35% in acute wounds and 58.70% in chronic wounds. The REMEDY provides a paradigm for converting nanoscale molecular operation to the microscale behaviors regulation and paves the pathway for advancing precise cell therapy in regenerative medicine.