Fe³⁺-Coordinated Multifunctional Elastic Nanoplatform for Effective in Vivo Gene Transfection

The common phenomenon that the nonviral vectors have much lower transfection efficiency in vivo than in vitro greatly restricts their further developments and applications. Possible reasons are lacking targeting ability, elimination by the reticuloendothelial system (RES), and insufficient nuclear transport. Here, a novel, flexible, and deformable polymer Fe@PEI-R12 (tLyp-1-NLS) is reported for shortening the gap between in vitro and in vivo gene transfection efficiency. The amorphous network structure Fe@PEI with deformation ability acquired by coordination cross-linking of Fe3+ and low-molecular-weight polyethylenimine (LMW-PEI) constructs the core and serves as the gene reservoir, and it can squeeze out through RES filter holes when trapped in the spleen. The bifunctional peptide R12 provided tumor targeting and enhanced nuclear delivery ability. Additionally, the Fe3+ from Fe@PEI-R12 could trigger endogenous hydrogen peroxide (H2O2) decomposition to produce O2, thereby reducing the adverse effects of tumor hypoxia. It is demonstrated that the Fe@PEI-R12/pDNA complexes could pass through membrane filters, subsequently achieving long circulation time, and Fe@PEI-R12 had a tendency to accumulate in tumor tissue and mediate pGL3-control expression. Therefore, the multifunctional nanoplatform has the potential for effective in vivo gene delivery.