Bioinspired synthesis of virus-like particle-templated thin silica-layered nanocages with enhanced biocompatibility and cellular uptake as drug delivery carriers

The bioinspired synthesis of virus-like silica nanoparticles in biomedical applications makes it possible to utilize the cellular delivery capabilities of viruses while minimizing the cytotoxicity of inorganic silica. In this study, we developed a diatom-inspired method for synthesizing silica-layered nanocages utilizing R5 peptide-functionalized virus-like particles (VLPs). R5 peptides were genetically inserted into the F-G loop of human papillomavirus 16 L1 proteins (HPV16 L1-R5). HPV16 L1-R5 was self-assembled into VLPs under an acidic pH similar to native ones and exhibited ∼65 % drug encapsulation efficiency. The HPV16 L1-R5 VLP@silica nanocages (SiNPs) were synthesized through diatom-inspired silicification of HPV16 L1-R5 VLPs via intermolecular interaction of the R5 peptide and polyol. HPV16L1-R5 VLP@SiNPs displayed uniform, monodisperse particles with approximately 10 nm silica layer compared to HPV16 L1-R5 VLPs. HPV16 L1-R5 VLP@SiNPs showed high biocompatibility at high concentrations, unlike commercial mesoporous SiNPs. Furthermore, the virus-like HPV16 L1-R5 VLP@SiNPs resulted in approximately 2.5-fold increased cellular uptake efficiency compared to commercial mesoporous SiNPs. These results suggest that the thin silica layer on HPV16 L1-R5 VLPs retains cellular delivery capacity while reducing cytotoxicity. Our strategy presents an innovative method for synthesizing virus-like nanoparticles in biomedical applications, enhancing cellular delivery capacity and biocompatibility.