Cellular Internalization–Induced Aggregation of Porous Silicon Nanoparticles for Ultrasound Imaging and Protein‐Mediated Protection of Stem Cells

Abstract Nanotechnology employs multifunctional engineered materials in the nanoscale range that provides many opportunities for translational stem cell research and therapy. Here, a cell‐penetrating peptide (virus‐1 transactivator of transcription)–conjugated, porous silicon nanoparticle (TPSi NP) loaded with the Wnt3a protein to increase both the cell survival rate and the delivery precision of stem cell transplantation via a combinational theranostic strategy is presented. The TPSi NP with a pore size of 10.7 nm and inorganic framework enables high‐efficiency loading of Wnt3a, prolongs Wnt3a release, and increases antioxidative stress activity in the labeled mesenchymal stem cells (MSCs), which are highly beneficial properties for cell protection in stem cell therapy for myocardial infarction. It is confirmed that the intracellular aggregation of TPSi NPs can highly amplify the acoustic scattering of the labeled MSCs, resulting in a 2.3‐fold increase in the ultrasound (US) signal compared with that of unlabeled MSCs. The translational potential of the designed nanoagent for real‐time US imaging–guided stem cell transplantation is confirmed via intramyocardial injection of labeled MSCs in a nude mouse model. It is proposed that the intracellular aggregation of protein drug–loaded TPSi NPs could be a simple but robust strategy for improving the therapeutic effect of stem cell therapy.