Framework Nucleic Acid‐Based Selective Cell Catcher for Endogenous Stem Cell Recruitment

Abstract Cell‐surface engineering holds great promise in boosting endogenous stem cell attraction for tissue regeneration. However, challenges such as cellular internalization of ligand and the dynamic nature of cell membranes often complicate ligand–receptor interactions. The aim of this study is to harness the innovative potential of programmable tetrahedral framework nucleic acid (tFNA) to enable precise, tunable ligand–receptor interactions, thereby improving stem cell recruitment efficiency. This approach involves experimental screening and theoretical analysis using dissipative particle dynamics. The results demonstrate that altering the flexibility and topology of ligands on tFNA changes their cellular internalization and membrane binding efficiency. Furthermore, optimizing the distribution of the mesenchymal stem cell (MSC)‐binding aptamer 19S (Apt19S) on the tFNA enhances the stem cell capture efficiency. Following successful in vitro MSC capture, Apt19S‐modified tFNA is chemically linked to a hyaluronic acid hydrogel, forming an efficient “stem cell catcher” system. Subsequent in vivo experiments demonstrate that this system effectively promotes early stem cell recruitment and accelerates bone regeneration in different bone healing scenarios, including cranial and maxillary defects.