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As emerging therapeutic factors, extracellular vesicles (EVs) offer significant potential for myocardial infarction (MI) treatment. Current delivery approaches for EVs involve either intra-myocardial or intravenous injection, where both have inherent limitations for downstream clinical applications such as secondary tissue injury and low delivery efficiency. Herein, an injection-free approach for delivering EVs onto the heart surface to treat MI is proposed. By spraying a mixture of EVs, gelatin methacryloyl (GelMA) precursors, and photoinitiators followed by visible light irradiation for 30 s, EVs are physically entrapped within the GelMA hydrogel network covering the surface of the heart, resulting in an enhanced retention rate. Moreover, EVs are gradually released from the hydrogel network through a combination of diffusion and/or enzymatic degradation of the hydrogel, and they are effectively taken up by the sprayed tissue area. More importantly, the released EVs further migrate deep into myocardium tissue, which exerts an improved therapeutic effect. In an MI-induced mice model, the group treated with EVs-laden GelMA hydrogels shows significant recovery in cardiac function after 4 weeks. The work demonstrates a new strategy for delivering EVs into cardiac tissues for MI treatment in a localized manner with high retention.

With the gradual demographic shift toward an aging and obese society, an increasing number of patients are suffering from bone and cartilage injuries. However, conventional therapies are hindered by the defects of materials, failing to adequately stimulate the necessary cellular response to promote sufficient cartilage regeneration, bone remodeling and osseointegration. In recent years, the rapid development of nanomedicine has initiated a revolution in orthopedics, especially in tissue engineering and regenerative medicine, due to their capacity to effectively stimulate cellular responses on a nanoscale with enhanced drug loading efficiency, targeted capability, increased mechanical properties and improved uptake rate, resulting in an improved therapeutic effect. Therefore, a comprehensive review of advancements in nanomedicine for bone and cartilage diseases is timely and beneficial. This review firstly summarized the wide range of existing nanotechnology applications in the medical field. The progressive development of nano delivery systems in nanomedicine, including nanoparticles and biomimetic techniques, which are lacking in the current literature, is further described. More importantly, we also highlighted the research advancements of nanomedicine in bone and cartilage repair using the latest preclinical and clinical examples, and further discussed the research directions of nano-therapies in future clinical practice. Graphical Abstract

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The chondron in articular cartilage includes the chondrocyte and its surrounding pericellular matrix (PCM). Single chondrocytes and chondrons were compressed between two parallel surfaces by a micromanipulation technique to investigate their biomechanical properties and to discover the mechanical significance of the PCM. The force imposed on the cells was measured directly during deformation at various compression speeds and deformations up to cell rupture. When the deformation at the end of compression was 50%, relaxation showed that the cells were viscoelastic, but this viscoelasticity was generally insignificant at 30% deformation or lower. When the deformation was 70%, the cells had deformed plastically. Chondrons ruptured at a mean deformation of 85 +/- 1%, whilst chondrocytes ruptured at a mean deformation of 78 +/- 1%. Chondrons were generally stiffer than chondrocytes and showed less viscoelastic behaviour than chondrocytes. Thus, the PCM significantly influences the mechanical properties of the cells.

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