PRP-activating hyaluronic acid hydrogels for immune-modulatory osteoarthritis repair.

Osteoarthritis (OA) is a prevalent whole-joint disease that requires effective disease-modifying therapies. Intra-articular platelet-rich plasma (PRP) injections offer a minimally invasive treatment option, but face two coupled challenges: premature ex vivo activation causes rapid growth-factor release before injection, and the inflamed, protease-rich synovial microenvironment accelerates their subsequent degradation. To address these barriers, we report an injectable dual-component hyaluronic acid (HA) hydrogel depot (PRP@Gel) that combines dynamic covalent HA-based delivery with a calcium-containing matrix designed to facilitate PRP activation and sustained immunomodulation. Distinct from conventional HA/PRP hydrogels that mainly improve local retention or deliver pre-activated PRP, PRP@Gel uses a calcium-integrated AHA-Ca backbone to support gradual post-injection PRP activation within the joint cavity, thereby limiting burst release of platelet-derived factors. Sustained calcitriol release concurrently promoted a tolerogenic DC phenotype in vitro and was associated with a shift from Th17-related responses toward Treg-related features. This immune modulation was associated with reduced MMP3 and CTSK expression, which may establish a less proteolytic microenvironment for PRP-derived factors. In a rat OA model, PRP@Gel treatment improved gait symmetry and cartilage integrity. Together, these findings support an integrated strategy that coordinates PRP activation with immune modulation to sustain regenerative signaling in OA joints.