Integrin–RGD Peptide Interaction Revisited: Bringing Integrin αvβ6 into Focus for Implications in Cancer Targeting

The RGD motif (Arg-Gly-Asp) mediates interaction with integrins, governing adhesion and signaling. Integrin αvβ6, an RGD-binding integrin, has gained attention as a therapeutic and diagnostic target because its expression is restricted in normal tissues yet markedly upregulated in pancreatic and colorectal cancer, where it is linked to poor prognosis. Although sequence identities across both subunits of examined integrin subtypes range from approximately 40% to 55%, structural analyses show that all integrins are highly similar, with an RMSD of less than 1.3 Å. This similarity underlies a conserved mechanism in which arginine and aspartate interact with the α-subunit and the β-subunit metal ion–dependent adhesion site (MIDAS), respectively, stabilizing ligand engagement. In line with this, αvβ6 follows the same recognition principle; however, its unique β6-specificity-determining loop provides an extra binding interface, enhancing affinity toward particular ligands. Herein, this perspective highlights the structural features of RGD-binding integrins, their interaction with linear and cyclic RGD-peptides, and approaches for improving specificity to αvβ6. Beyond the RGD motif, linker design, including spacer length, bioconjugation chemistry, and stimuli-responsive cleavable motifs with self-immolative spacers, balances plasma stability with tumor-specific, traceless payload release, determining the pharmacological behavior of cyclic RGD–nanoparticle conjugates and their adaptation to future delivery and radiotracer platforms.