Engineering natural arginine finger to deliver phosphate-containing drugs for treating osteoarthritis

Molecular assembly of biomimetic peptides can simulate complex protein domains, providing innovative approaches to drug delivery. In this study, we designed a series of arginine finger peptides (AFP1-6) mimicking the natural arginine finger (R-finger) motifs, which specifically recognize and bind phosphate substrates, and developed a co-assembling strategy to effectively deliver phosphate-containing drugs (PCDs). Among these arginine finger peptides, AFP2 co-assembled with various clinically approved PCDs into nanofibers through R-finger-phosphate recognition, forming stable hydrogels with enhanced stability, high biocompatibility, and sustained release profiles of PCDs both in vitro and in vivo. Using spectral analysis and simulation tools, we elucidated the molecular mechanisms underlying their assembling behaviors, which aligned closely with experimental observations. Furthermore, we developed a co-assembling hydrogel (AFP2@DV) co-loaded with dexamethasone phosphate and vitamin C phosphate for combination therapy in osteoarthritis. A single-dose administration of the AFP2@DV hydrogel significantly alleviated osteoarthritis symptoms and protected chondrocytes in vivo. This R-finger motif-guided peptide assembly highlights the significance of transforming protein domains into functional biomaterials for therapeutic applications.