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Background: Reactive oxygen species (ROS) is considered as ubiquitous and highly active chemicals that influence tendon integrity and orchestrate tendon repair. With significant recent advances in nanomaterials, cerium oxide nanoparticles (CeO2 NPs) exhibit superoxide dismutase- and catalase-like activities. Herein, we introduced a therapeutic approach of CeO2 NPs for Achilles tendinopathy (AT) healing. Methods: CeO2 NPs were synthesized to examine their effect as ROS scavengers on AT healing in vitro and in vivo. The mRNA levels of inflammatory factors were evaluated in AT after CeO2 NPs treatment in vitro. The mechanisms underlying CeO2 NPs-mediated stimulation of NRF2 translocation and ERK signaling were verified through immunofluorescence and Western blot analysis. The efficacy of CeO2 NPs was tested in an AT rat model in comparison with the control. Results: CeO2 NPs not only significantly scavenged multiple ROS and suppressed ROS-induced inflammatory reactions but also protected cell proliferation under oxidative stress induced by tert-butyl hydroperoxide (TBHP). Moreover, CeO2 NPs could promote NRF2 nuclear translocation for anti-oxidation and anti-inflammation through the ERK signaling pathway. In a rat model of collagenase-induced tendon injuries, CeO2 NPs showed significant therapeutic efficacy by ameliorating tendon damage. Conclusion: The present study provides valuable insights into the molecular mechanism of CeO2 NPs to ameliorate ROS in tenocytes via the ERK/NRF2 signaling pathway, which underscores the potential of CeO2 NPs for application in the treatment of enthesopathy healing.
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