Rational Synthesis of Virus-Mimicking Nanocarriers for Enhanced Intracellular Delivery through Polyvalent Interactions with Cells

It remains a grand challenge to rationally design and synthesize nanocarriers with well-controlled surface properties to manipulate their interactions with cells and intracellular trafficking. Here, we report a rational synthesis of virus-mimicking nanocarriers characterized by a controlled number of hydrophobic protrusions on the hydrophilic surface. When a polystyrene bead is coated with a porogen-loaded SiO2 shell and then exposed to a good solvent, the polymer is swollen to generate an internal pressure against the shell. By adjusting the extent of porogen removal, the swollen polymer can push through the shell from one, two, or multiple sites to create up to 175 hydrophobic protrusions while leaving behind a cavity inside the shell. As the number of protrusions increases, polyvalent interactions with lipid bilayer are enabled and enhanced to promote both cellular uptake and endo/lysosomal escape. By leveraging the mesopores in the wall, the cavity can be readily loaded with various types of drugs for cytoplasmic delivery at maximal therapeutic efficacy. This work offers a rational approach to the development of advanced nanocarriers for biomedicine.