Third-degree, large-area skin injuries impose a significant socioeconomic burden on victims each year. The liver demonstrates extensive regenerative properties, and its exosomes are rich in organic selenium protein (SELENOP) with a high bioavailability. In this study, we established hepatic exosomes as a distinct biological nanoparticle and considering its unique cargo to investigate their regenerative effects on skin cells, including upregulation of cell growth, antioxidant molecules, and angiogenic properties, which have not been previously explored. Building on these promising findings, we designed a novel three-dimensional (3D) bio-printed multicellular skin organoid scaffold using hepatic exosome-encapsulated GECM (GelMa-ECM) bio-ink to mimic native skin structure. In vivo, the skin construct orchestrates wound healing by boosting key tissue regenerative markers, biological processes, and signaling pathways, while also downregulating various pro-inflammatory pathways during the proliferative stage of healing. Our study highlights a new strategy for wound healing and offers potential insights into the treatment of other chronic and recalcitrant skin diseases.

Osteoarthritis (OA) is a common degenerative disease worldwide and new therapeutics that target inflammation and the crosstalk between immunocytes and chondrocytes are being developed to prevent and treat OA. These attempts involve repolarizing pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in synovium. In this study, we found that phosphoglycerate mutase 5 (PGAM5) significantly increased in macrophages in OA synovium compared to controls based on histology of human samples and single-cell RNA sequencing results of mice models. To address the role of PGAM5 in macrophages in OA, we found conditional knockout of PGAM5 in macrophages greatly alleviated OA symptoms and promoted anabolic metabolism of chondrocytes in vitro and in vivo. Mechanistically, we found that PGAM5 enhanced M1 polarization via AKT-mTOR/p38/ERK pathways, whereas inhibited M2 polarization via STAT6-PPARγ pathway in murine bone marrow-derived macrophages. Furthermore, we found that PGAM5 directly dephosphorylated Dishevelled Segment Polarity Protein 2 (DVL2) which resulted in the inhibition of β-catenin and repolarization of M2 macrophages into M1 macrophages. Conditional knockout of both PGAM5 and β-catenin in macrophages significantly exacerbated osteoarthritis compared to PGAM5-deficient mice. Motivated by these findings, we successfully designed mannose modified fluoropolymers combined with siPGAM5 to inhibit PGAM5 specifically in synovial macrophages via intra-articular injection, which possessed desired targeting abilities of synovial macrophages and greatly attenuated murine osteoarthritis. Collectively, these findings defined a key role for PGAM5 in orchestrating macrophage polarization and provides insights into novel macrophage-targeted strategy for treating OA.