Bioinspired Silicification of mRNA-Loaded Polyion Complexes for Macrophage-Targeted mRNA Delivery

In vitro transcribed messenger RNA (mRNA) delivery to macrophages is a promising therapeutic modality for inflammatory diseases because it can modulate the immunological activity of macrophages. However, efficient macrophage-targeted mRNA delivery remains challenging. Herein, we fabricated silica-coated polyion complexes (PICs), termed SilPICs, via bioinspired silicification for stable encapsulation of mRNA and scavenger receptor (SR)-mediated macrophage targeting. Silica coating was readily performed by simply mixing mRNA-loaded PICs with tetramethyl orthosilicate in aqueous media at 25 °C. The silica shell formation was verified by a slight increase in size (∼18 nm), a conversion of ζ-potential from positive (+22 mV) to negative (-23 mV), the peak appearance derived from silanol groups and siloxane bonds in the IR spectra, and elemental analyses by scanning transmission electron microscopy-energy-dispersive X-ray spectrometry (STEM-EDS). The silica shell efficiently protected the mRNA payload from enzymatic degradation in a fetal bovine serum-containing medium. Meanwhile, the reversibility of the silica shell allowed mRNA release from SilPICs after silica dissolution into silicic acids under diluted conditions. Furthermore, SilPICs elicited 20-fold higher mRNA transfection efficiency in the macrophage cell line RAW264.7 compared to noncoated PICs, presumably due to the facilitated cellular internalization by the silica shell. These enhancements were compromised in the RAW264.7 cells incubated with dextran sulfate and poly(inosinic acid) as inhibitors of SR type A1 and were not observed in cultured CT26 colon cancer cells, which are SR-negative cells. Collectively, SilPIC is a promising mRNA delivery vehicle with both mRNA protectability and macrophage targetability.