Protein nanogels with enhanced pH-responsive dynamics triggered by remote NIR for systemic protein delivery and programmable controlled release

Therapeutic proteins represent promising treatments in medical applications; however, direct administration of native proteins frequently suffers from in vivo enzymatic degradation or denaturation in hostile environments. Engineering proteins into biocompatible formulations can be used to solve these problems. Despite years of effort, efficient systemic delivery followed by successful release from the formulation remains a challenge. Herein, we describe a pH-responsive nanogel (PI825@PDC/protein NGs) formed by host-guest recognition of 6arm PEGylated crystalline beta-cyclodextrin (beta-CD) and near-infrared IR825 dye, which affords highly efficient encapsulation of proteins during their self-assembly. PI825@PDC/protein NGs are robust enough to withstand hostile physiological conditions both in vitro and in vivo and could be slightly disassociated from protein release in acidic environments due to the anchored pH-responsive 2,3-dimethylmaleic anhydride (DMA) linker. Furthermore, the pH-responsive dynamics can be greatly enhanced by elevated temperature upon remote (Nearinfrared spectroscopy) NIR irradiation of the IR825 within NGs, generating programmable release of loaded proteins for enhanced cancer treatment. This study describes a general method to load proteins with high efficiency for systemic delivery, followed by programmable protein release by remote NIR irradiation and offers new insights for protein engineering and potential medical applications.

Automated summary

Therapeutic proteins can be engineered into biocompatible formulations for efficient encapsulation and programmable release using a pH-responsive nanogel, offering new insights for potential medical applications, particularly in cancer treatment.