Tendon aging is frequently accompanied by extrinsic inflammation-aging harassment and intrinsic TSPC senescence, resulting in impaired reparative and regenerative capacities. [2] Although the functional decline of senescent TSPCs is accepted well, an efficient and precise method to rejuvenate aged TSPC (AT-SC) function and recover aging-impaired tendon reparative capacity remains to be further explored.Extracellular vesicles (EVs) are membrane-enclosed structures mainly that are classified into two main groups: exosomes and microvesicles. Among them, exosomes range from 40 to 150 nm in diameter and are mainly derived from the endosomal system, [3] whereas microvesicles range from 100 to 1000 nm in diameter and are generated by shedding of the plasma membrane. EVs could facilitate intercellular communication by transferring mRNA, microRNA, proteins, and organelle cargoes into recipient cells; [4] therefore, EVs have been suggested as excellent candidates for therapeutic methods for tissue regeneration and repair. Recently, EVs have been proven to be beneficial components of young blood in extending the life span of mice, suggesting that some specific EVs may possess an anti-senescent function. [5] Aging impairs tendon stem/progenitor cell function and tendon homeostasis, however, effective treatments for aging-induced tendon diseases are lacking. Exosomes are naturally derived nanoparticles that contain bioactive molecules, and therefore, have attracted great interest in tissue engineering and regenerative medicine. In this study, it is shown that young exosomes secreted by stem cells from human exfoliated deciduous teeth (SHED-Exos) possess abundant anti-aging signals. These young bio-nanoparticles can alleviate the aging phenotypes of aged tendon stem/progenitor cells (AT-SCs) and maintain their tenogenic capacity. Mechanistically, SHED-Exos modulate histone methylation and inhibit nuclear factor-κB to reverse AT-SC aging. In a naturally aging mouse model, systemic administration of SHED-Exo bio-nanoparticles retards tendon degeneration. Interestingly, local delivery of SHED-Exos-loaded microspheres confers anti-aging phenotypes, including reduced senescent cells and decreased ectopic bone formation, thereby functionally and structurally rescuing endogenous tendon regeneration and repair capacity in aged rats. Overall, SHED-Exos, as natural bioactive nanoparticles, have promising translational and therapeutic potential for aging-related diseases.

Macrophages are involved mainly in the balance between inflammation and tenogenesis during the healing process of tendinopathy. However, etiological therapeutic strategies to efficiently treat tendinopathy by modulating macrophage state are still lacking. In this study, we find that a small molecule compound Parishin-A (PA) isolated from Gastrodia elata could promote anti-inflammatory M2 macrophage polarization by inhibiting gene transcription and protein phosphorylation of signal transducers and activators of transcription 1. Local injection or sustained delivery of PA by mesoporous silica nanoparticles (MSNs) could almost recover the native tendon’s dense parallel-aligned collagen matrix in collagenase-induced tendinopathy by modulating macrophage-mediated immune microenvironment and preventing heterotopic ossification. Especially, MSNs decrease doses of PA, frequency of injection and yield preferable therapeutic effects. Mechanistically, intervention with PA could indirectly inhibit activation of mammalian target of rapamycin to repress chondrogenic and osteogenic differentiation of tendon stem/progenitor cells by influencing macrophage inflammatory cytokine secretion. Together, pharmacological intervention with a natural small-molecule compound to modulate macrophage status appears to be a promising strategy for tendinopathy treatment.

Macrophages are involved mainly in the balance between inflammation and tenogenesis during the healing process of tendinopathy. However, there is still lack of etiological therapeutic strategies to modulate macrophage state to treat tendinopathy efficiently. Here, we find that a small molecule compound Parishin-A (PA) isolated from Gastrodia elata could promote anti-inflammatory M2 macrophage polarization by inhibiting gene transcription and protein phosphorylation of signal transducers and activators of transcription 1. Local injection or sustained delivery of PA by mesoporous silica nanoparticles (MSNs) could almost recover the native tendon’s dense parallel-aligned collagen matrix in collagenase-induced tendinopathy by modulating macrophage-mediated immune microenvironment and preventing heterotopic ossification. Especially, MSNs decrease doses of PA, frequency of injection and yield preferable therapeutic effects. Mechanistically, intervention with PA could indirectly inhibit activation of mammalian target of rapamycin to repress chondrogenic and osteogenic differentiation of tendon stem/progenitor cells by influencing macrophage inflammatory cytokine secretion. Together, pharmacological intervention with natural small-molecule compound to modulate macrophage status appears to be a promising strategy for tendinopathy treatment.