The combined use of AuNP and NIR radiation enables cytosolic protein delivery

Cytosolic protein delivery remains elusive. The instability of proteins in the endosomal/lysosomal environment and their inability to cross the endosomal membrane are two major bottlenecks. Here we explore the unique photothermal properties of gold nanorods (AuNRs) to trigger cytosolic delivery of proteins. Both partners, protein and AuNRs, are modified with a protease-resistant cell-penetrating peptide with nuclear targeting properties, to induce internalization. Once internalised, spatiotemporal control of protein release is securely achieved by near-infrared laser irradiation in the safe second biological window. Importantly, catalytic amounts of AuNRs are sufficient to trigger cytosolic protein delivery. To the best of our knowledge, this is the first time that AuNRs with their maximum of absorption in the second biological window are used to deliver proteins into the cytosol. This strategy represents a powerful tool for the intracellular delivery of virtually any class of protein.