Abstract
The inflammatory microenvironment mediated by synovial macrophages, particularly the pro-inflammatory M1 subtype, plays a central role in OA progression and represents a critical therapeutic target. However, delivery strategies that enable efficient and selective targeting of M1 macrophages for modulating the inflammatory microenvironment are still limited. To address this challenge, we developed a glucose-functionalized nanoparticle system (Ber-MNPs) to deliver berberine directly to pro-inflammatory M1 subtype macrophages-via GLUT1-mediated targeting, thereby modulating the inflammatory microenvironment to alleviate OA progression. The Ber-MNPs exhibited excellent targeting specificity toward M1 macrophages in vitro. In addition, Ber-MNPs can suppress macrophage polarization toward the pro-inflammatory M1 phenotype, promote their transition to the anti-inflammatory M2 phenotype, and downregulate inflammatory cytokines, thereby protecting chondrocytes from catabolic damage. In a surgically induced OA mouse model, intra-articularly administered Ber-MNPs exhibited prolonged joint retention and mitigated OA progression by attenuating synovial inflammation and preserving cartilage integrity. Together, this study establishes a M1 macrophage-targeted nanotherapeutic platform that achieves precise inflammatory modulation, offering a new strategy for reshaping the synovial inflammatory microenvironment and achieving effective delay of OA progression.