M1 macrophage-targeted glucose-functionalized nanoparticles for berberine delivery and inflammatory microenvironment remodeling in osteoarthritis therapy

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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 Scheme 1. Schematic illustration of berberine-loaded M1 macrophage-targeted nanoparticles (Ber-MNPs) for the treatment of OA. Ber-MNPs suppress the production of pro-inflammatory factors—such as TNF-α, iNOS, IL-6, and ROS—in synovial M1 macrophages, while promoting the repolarization of M1 toward M2 macrophages, thereby protecting against cartilage degradation. Abbreviation: OA: Osteoarthritis; Col2α1: Collagen Type II α1 Chain; Acan: Aggrecan; Arg1: Arginase 1; MMP-13: Matrix Metalloproteinase-13; TNF-α: Tumor Necrosis Factor-α; iNOS: inducible Nitric Oxide Synthase; ROS: Reactive Oxygen Species; IL-6: Interleukin-6.

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