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

ABSTRACT

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.