Cartilage-targeting mRNA-lipid nanoparticles rescue perifocal apoptotic chondrocytes for integrative cartilage repair

[Display omitted] •CAQK targets not only injured brain, but also cartilage.•Successfully developed mRNA-cLNP to enhance cartilage-cartilage integration.•mRNA-cLNP penetrates cartilage and extends residence time.•mRNA-cLNP maintains perifocal cellularity and ECM biosynthesis.•Modified mRNA transfer produced IGF-1 protein with higher anti-apoptosis activity than recombinant IGF-1. Integration of repair tissue with host cartilage is challenging. The persistent and drastic hypocellular interface resulting from perifocal chondrocyte apoptosis, leads to failure of cartilage repair over time. Recombinant insulin-like growth factor-1 (IGF-1) has been shown to inhibit chondrocyte apoptosis in vitro. However, low bioactivity, limited penetration and short retention are its drawbacks. Herein, a cartilage targeting ionizable lipid nanoparticle (LNP) is developed. Messenger RNA (mRNA) encoding IGF-1 is chemically modified and encapsulated by LNP (mRNA-LNP). CAQK, a peptide previously used for targeted delivery to the central nervous system, is introduced to mRNA-LNP (mRNA-cLNP) to bind aggrecan enriched in cartilage. As a result, mRNA-cLNP exhibits improved penetration of cartilage and prolonged retention in the joint cavity. The mRNA-cLNP also showed robust reversal of chondrocyte apoptosis. In a full-thickness chondral defect plus microfracture model, mRNA-cLNP maintained interfacial cellularity and prevented matrix degradation in cartilage-cartilage interface. This study shows that mRNA-cLNP is a promising therapeutic agent for integrative cartilage repair.