Fig. 1.

Biological barriers faced by nanoparticles. (I) After injection, proteins in plasma accumulate on the surface of nanoparticles and form a protein corona that can change the interactions of nanoparticles with the biological environment. (II) Phagocytic cells detect nanoparticles because of the protein corona and remove them from the circulation. (III) Heterogeneous vascular leakage causes nonuniform distribution of nanoparticles in the tumor. In addition, high intra-tumor IFP reduces convection, limiting delivery into the tissue. (IV) After extravasation, dense ECM and high IFP are barriers against nanoparticle penetration. (V) Finally, cell membranes, which act as a shell to protect cellular organelles, resist the penetration of nanoparticles into the cell during the internalization process.