A microsphere loaded with chondrocyte-targeting exosomes continuously deliver miR-148a for osteoarthritis therapy

Due to the complex pathogenesis and limited treatment options, the clinical diagnosis and treatment of osteoarthritis (OA) remains extremely challenging. Umbilical cord derived mesenchymal stem cell-derived exosomes have low immunogenicity, high biocompatibility and superior transbiofilm properties, showing great research value in OA treatment. Healthy chondrocytic extracellular matrix anabolism is essential for cartilage homeostasis. The abnormal reduction of miR-148a in chondrocytes impairs extracellular matrix anabolism, accelerating the progression of OA. Therefore, increasing miR-148a in chondrocytes is a potential OA treatment strategy. However, the dense extracellular matrix in articular cartilage hinders the delivery of exosomes and microRNAs, in addition to their short retention time <i>in vivo</i> greatly limits their clinical application. Herein, a biodegradable microsphere loaded with chondrocyte targeting exosomes (CAP-EXOs/miR-148a@GAM) was developed for sustained delivery of miR-148a. Firstly, we synthesized microspheres (GAM) with methacrylated gelatin and streptavidin by microfluidic system, and then loaded miR-148a into exosomes modified with chondro-targeting peptide CAP (CAP-EXOs) and encapsulated it into GAM to obtain CAP-EXOs/miR148a@GAM. The <i>in-vitro</i> results show that this microsphere promotes the anabolism of chondrocytes and exhibits satisfactory performance in maintaining cartilage homeostasis. The <i>in-vivo</i> experiments show that the microspheres can effectively delay the degeneration of osteoarthritic cartilage. Collectively, this study presents a multifunctional paradigm of nucleic acid drug delivery for the treatment of OA.