Challenges in the Therapeutic Exploitation of Chemokine Receptor-Mediated Internalization of Nanocarriers

Chemokines are small proteins guiding cell migration with crucial role during immune responses. Their actions are mediated by 7-helix trans-membrane Gα protein-coupled receptors and ended by chemokine-receptor complex downregulation. Beyond its physiological role, ligand-induced receptor endocytosis can be exploited to vehiculate drugs and genetic materials within specific cells. Indeed, peptide-modified drugs and chemokine-decorated nanocarriers can target cell subpopulations significantly increasing cargo internalization. Carrier functionalization with small peptides or small-molecule-antagonists have been developed by different groups and proved their efficacy in vivo. One major limitation regards their restricted number of targeted receptors, although involved in diverse types of cancer and inflammatory diseases. Our group implemented nanoparticle decoration using whole chemokines, which in my opinion offer a versatile platform for precise drug delivery. The rationale relies on the broad and distinctive cellular expression of all chemokine receptors covering the different tissues, theoretically allowing chemokine-decorated particle delivery to any chosen cell subset. Although promising, our approach is still in its infancy and the experiments performed only in vitro so far. This manuscript briefly describes the established nanotechnologies for chemokine receptor-mediated delivery and, in greater details, our chemokine-decorated nanoparticles. Positive and negative aspects of the different approaches are also discussed, giving my opinion on why future nano-formulations could benefit from these chemo-attractant immune mediators.