Achilles tendon rupture prognosis is usually unsatisfactory. After the tendon is injured, it may not function properly because of the fibrotic healing response, which restrains tendon motion. Inflammatory monocytes and tissue-resident macrophages are indispensable regulators in tissue repair, fibrosis, and regeneration. Exosomes from macrophages are crucial factors in tissue microenvironment regulation following tissue injury. This study therefore aimed to clarify the roles of macrophage exosomes in tendon injury (TI) repair. The results show that macrophages play a role after TI. M1 macrophages were increased relative to peritendinous fibrosis after TI. High-throughput sequencing showed abnormal expression of circular RNAs (circRNAs) between exosomes from M2 and M0 macrophages. Among the abnormal expressions of circRNA, circRNA-Ep400 was significantly increased in M2 macrophage exosomes. The results also show that M2 macrophage-derived circRNA-Ep400-containing exosomes are important for promoting peritendinous fibrosis after TI. Bioinformatics and dual-luciferase reporting experiments confirmed that miR-15b-5p and fibroblast growth factor (FGF)-1/7/9 were downstream targets of circRNA-Ep400. High circRNA-Ep400-containing exosome treatment inhibited miR-15b-5p, but promoted FGF1/7/9 expression in both fibroblasts and tenocytes. Furthermore, high circRNA-Ep400-containing exosome treatment promoted fibrosis, proliferation, and migration in both fibroblasts and tenocytes. Taken together, the results show that M2 macrophage-derived circRNA-Ep400-containing exosomes promote peritendinous fibrosis after TI via the miR-15b-5p/FGF-1/7/9 pathway, which suggests novel therapeutics for tendon injury treatment.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a disease characterized by the collapse of the femoral head. SONFH occurs due to the overuse of glucocorticoids (GCs) in patients with immune-related diseases. Among various pathogenesis proposed, the mechanism related to impaired blood vessels is gradually becoming the most convincing hypothesis. Bone endothelial cells including bone microvascular endothelial cells (BMECs) and endothelial progenitor cells (EPCs) play a crucial role in the maintenance of vascular homeostasis. Therefore, bone endothelial cells are key regulators in the occurrence and progression of SONFH. Impaired angiogenesis, abnormal apoptosis, thrombosis and fat embolism caused by the dysfunctions of bone endothelial cells are considered to be the pathogenesis of SONFH. In addition, even with high disability rates, SONFH lacks effective therapeutic approach. Icariin (ICA, a flavonoid extracted from Epimedii Herba), pravastatin, and VO-OHpic (a potent inhibitor of PTEN) are candidate reagents to prevent and treat SONFH through improving above pathological processes. However, these reagents are still in the preclinical stage and will not be widely used temporarily. In this case, bone tissue engineering represented by co-transplantation of bone endothelial cells and bone marrow mesenchymal stem cells (BMSCs) may be another feasible therapeutic strategy.

Fabrication of nanotheranostic agents attracted a growing interest in accurate diagnosis and therapy of cancer by the sustainable biomineralization strategy. Herein, it is reported that biomineralized cobalt sulfide nanodots (Co 9 S 8 NDs) with intrinsic peroxidase-like activity are potentially useful for synergetic phototherapy with tumor multimodal imaging navigation. The multifunctional Co 9 S 8 NDs are first synthesized in aqueous phase via a simple biomineralization route. Detailed characterization reveals that the constructed peroxidase-like Co 9 S 8 NDs not only possess strong paramagnetism with near-infrared absorption but also generate reactive oxygen species via photocatalytic reaction. As a result, the Co 9 S 8 NDs reveal excellent performance for magnetic resonance and photoacoustic imaging of tumors, and outstanding tumor ablation efficiency owing to the near-infrared responsive photodynamic and photothermal effect. To our knowledge, ultrasmall Co 9 S 8 NDs via aqueous phase synthesis have not been reported for multimodal theranostic applications so far.

Emerging nanomedical strategy is to construct a nanoagent that affords not only diagnostic and therapeutic functions but also imaging-guided treatment. It is crucial to understand the in vivo biological processes of nanoagents for improving theranostic function and biosafety. Herein, we report a multimodal photoacoustic/single-photon emission computed tomography (SPECT) imaging technique to dynamically monitor the in vivo behaviors of nanoagents. Near-infrared cypateinduced silk fibroin nanoassembly was chosen as the nanoagent object due to their promise in biocompatibility and aggregationenhanced photothermal effect. This unique effect makes the nanoagents useful for the integration of photoacoustic imaging and photothermal therapy. Moreover, the nanoagents are also labeled with the radionuclides ( 99m Tc) to render SPECT imaging. Multimodal photoacoustic/SPECT imaging provides real time, noninvasive, sensitive, and whole-body 3D information about nanoagents' distribution in vivo. These results highlight the significance of visualizing the in vivo behaviors of nanoagents and locating the tumor in vivo, substantially benefiting the better treatment planning.