Fmoc-DDT@Fos hydrogel mitigates temporomandibular joint osteoarthritis through regulating macrophage reprogramming and ferroptosis.

Temporomandibular joint osteoarthritis (TMJ OA) represents a progressive degenerative disorder that seriously threatens patients' quality of life. Current treatment aims to slow cartilage degeneration, relieve pain, promote bone remodeling, and restore joint function. In this study, we develop a novel peptide hydrogel drug delivery system named Fmoc-DDT@Fos, combining Fmoc-FF peptides with PLGA/TPP nanospheres loaded with Fostamatinib (Fos), functionalized for sustained release and locally targeted application of Fos. In vitro and in vivo studies demonstrate that this drug delivery system has good biocompatibility, macrophage targeting, and Fos slow-release properties. It is able to inhibit inflammatory response by promoting the functional reprogramming of macrophages from pro-inflammatory M1 phenotype toward anti-inflammatory M2 phenotype and modulating ferroptosis pathways, which subsequently maintains condylar cartilage homeostasis and halts TMJ OA progression. By elucidating these mechanisms, our research not only offers a novel therapeutic strategy for TMJ OA but also deepens our understanding of its pathophysiology. Moreover, this biomaterial-based strategy may provide a safer and more effective framework for managing other inflammatory and degenerative diseases.