Cell-free fat extract-loaded microneedles attenuate inflammation-induced apoptosis and mitochondrial damage in tendinopathy

Existing clinical treatments for tendinopathy mainly focus on reducing pain, whereas inhibiting or reversing disease progression remains challenging. Local therapeutic drugs, such as glucocorticoids, cause adverse effects on the metabolism of tendon tissues and injection-related complications. Therefore, new administration modalities for tendinopathy need to be developed. In this study, we designed a hydrogel-based microneedle (MN) system for the long-term transdermal delivery of our novel biological cell-free fat extract (CEFFE) to treat tendinopathies. We found that CEFFE-loaded MNs (CEFFE-MNs) had good biosafety and inhibited lipopolysaccharide (LPS)-induced apoptosis and matrix degradation in Achilles tendon cells of rats. The Achilles tendons of rats returned to their maximum mechanical strength after applying CEFFE-MNs. The administration of CEFFE-MNs had better anti-apoptosis and tendon repair-promoting effects than CEFEF injections in vivo. Transcriptome sequencing indicated that the anti-apoptosis effect of CEFFE-MNs was highly related to tumor necrosis factor (TNF) signaling. CEFFE-MNs inhibited the expression of TNF, TNF receptor 1, and downstream nuclear factor-kappa B signaling. Additionally, CEFFE-MNs rescued LPS-induced mitochondrial dynamics in tendon cells via the TNF-Drp1 axis. Our study reports a novel CEFFE-MN system that exhibits long-term anti-inflammatory and anti-apoptotic effects, suggesting it as a new treatment route for tendinopathy with broad clinical translation prospects.