Inflammation-Responsive Nanocolloidal Hydrogel Enables On-Demand Gene Activation for Osteoarthritis Therapy.

Synovitis-driven inflammation and oxidative stress are key drivers of osteoarthritis (OA) progression. As a master regulator of antioxidant and anti-inflammatory defenses, nuclear factor erythroid 2-related factor 2 (Nrf2) represents a promising therapeutic target. However, current strategies for Nrf2 activation remain limited in achieving durable synovial gene expression and pathology-adaptive release. Here, we developed an injectable inflammation-responsive nanocolloidal hydrogel enabling sustained and on-demand Nrf2 activation within OA joints. The hydrogel was fabricated by crosslinking polyvinyl alcohol (PVA) with phenylboronic acid (PBA)-functionalized nanoparticles encapsulating Nrf2 plasmids. Dynamic boronate ester linkages between PBA and PVA enabled rapid in situ gelation after intra-articular injection. In the ROS-enriched inflammatory microenvironment of OA, cleavage of boronate ester bonds triggered the release of Nrf2 plasmid-loaded nanoparticles. The released nanoparticles were efficiently internalized by fibroblast-like synoviocytes (FLSs) and promoted Nrf2 expression, thereby suppressing oxidative stress and inflammatory responses. In ACLT-induced OA mice, the hydrogel markedly alleviated synovial inflammation, preserved cartilage matrix, and reduced the OARSI score by approximately 70%. These findings highlight its potential as a promising strategy for inflammation-adaptive gene regulation in OA therapy.