Unsatisfactory post-stroke recovery has long been a negative factor in the prognosis of ischemic stroke due to the lack of pharmacological treatments. Mesenchymal stem cells (MSCs)-based therapy has recently emerged as a promising strategy redefining stroke treatment; however, its effectiveness has been largely restricted by insufficient therapeutic gene expression and inadequate cell numbers in the ischemic cerebrum. Herein, a non-viral and magnetic field-independent gene transfection approach is reported, using magnetosome-like ferrimagnetic iron oxide nanochains (MFIONs), to genetically engineer MSCs for highly efficient post-stroke recovery. The 1D MFIONs show efficient cellular uptake by MSCs, which results in highly efficient genetic engineering of MSCs to overexpress brainderived neurotrophic factor for treating ischemic cerebrum. Moreover, the internalized MFIONs promote the homing of MSCs to the ischemic cerebrum by upregulating CXCR4. Consequently, a pronounced recovery from ischemic stroke is achieved using MFION-engineered MSCs in a mouse model.

Neural stem cells (NSCs), capable of ischemia‐homing, regeneration, and differentiation, exert strong therapeutic potentials in treating ischemic stroke, but the curative effect is limited in the harsh microenvironment of ischemic regions rich in reactive oxygen species (ROS). Gene transfection to make NSCs overexpress brain‐derived neurotrophic factor (BDNF) can enhance their therapeutic efficacy; however, viral vectors must be used because current nonviral vectors are unable to efficiently transfect NSCs. The first polymeric vector, ROS‐responsive charge‐reversal poly[(2‐acryloyl)ethyl(p‐boronic acid benzyl)diethylammonium bromide] (B‐PDEA), is shown here, that mediates efficient gene transfection of NSCs and greatly enhances their therapeutics in ischemic stroke treatment. The cationic B‐PDEA/DNA polyplexes can effectively transfect NSCs; in the cytosol, the B‐PDEA is oxidized by intracellular ROS into negatively charged polyacrylic acid, quickly releasing the BDNF plasmids for efficient transcription and secreting a high level of BDNF. After i.v. injection in ischemic stroke mice, the transfected NSCs (BDNF‐NSCs) can home to ischemic regions as efficiently as the pristine NSCs but more efficiently produce BDNF, leading to significantly augmented BDNF levels, which in turn enhances the mouse survival rate to 60%, from 0% (nontreated mice) or ≈20% (NSC‐treated mice), and enables more rapid and superior functional reconstruction.

Gene delivery to stem cells is a critical issue of stem cells‐based therapies, still facing ongoing challenges regarding efficiency and safety. Recent advances in the controlled synthesis of biocompatible magnetic iron oxide nanoparticles (IONPs) have provided a powerful nanotool for assisting gene delivery to stem cells. However, this field is still at an early stage, with well‐designed and scalable IONPs synthesis highly desired. Furthermore, the potential risks or bioeffects of IONPs on stem cells are not completely figured out. Therefore, in this review, the updated researches focused on the gene delivery to stem cells using various designed IONPs are highlighted. Additionally, the impacts of the physicochemical properties of IONPs, as well as the magnetofection systems on the gene delivery performance and biocompatibility are summarized. Finally, challenges attributed to the potential impacts of IONPs on the biologic behaviors of stem cells and the large‐scale productions of uniform IONPs are emphasized. The principles and challenges summarized in this review provide a general guidance for the rational design of IONPs‐assisted gene delivery to stem cells.

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