上海科技大学知识管理系统

Lipid nanoparticle (LNP)-mRNA is a promising therapeutic strategy for various diseases via indirectly delivering therapeutic proteins effectively. Drug delivery to chondrocytes is challenging because it requires penetration of the densely packaged extracellular matrix (ECM) of cartilage and then distribution in its microenvironment. In this work, we discovered the remarkable capability of LNPs to permeate deeply in the cartilage tissue, penetrating depths exceeding 100 μm within the mouse knee joint, i.e. five-fold deeper than direct protein delivery to cartilage. Motivated by this discovery, we optimized the mRNA structure and LNP formulation for the chondrocytes and obtained persistent protein expression in the knee joints. The mRNA encoding single-chain adalimumab (ADA) was further packaged by LNP and delivered to the knee joint to neutralize the TNF-α in osteoarthritis (OA) cartilage. Ultimately, our investigation confirmed that cartilage-optimized adalimumab mRNA-LNP effectively inhibits the TNF-α-induced inflammation and ECM degradation in vitro and demonstrates significant protective effects against destabilization of the medial meniscus (DMM) surgery-induced OA in vivo. Collectively, our study reveals a promising therapeutic strategy for the treatment of OA. © 2024 Elsevier B.V.