Multifunctional Prussian lue nanozymes ameliorate tendinopathy via modulating tissue homeostasis.

Tendinopathy, a prevalent musculoskeletal disorder characterized by chronic pain and functional decline, remains a therapeutic challenge due to the limited efficacy of conventional treatments in addressing oxidative stress and persistent inflammation. Here, we present Prussian blue nanozymes (PBzymes) as a catalytic nanomedicine engineered to mimic multi-enzyme activities, offering a potent strategy for tendon microenvironment modulation and repair. Synthesized via a hydrothermal template-free approach, PBzymes exhibit robust reactive oxygen species (ROS)-scavenging capabilities through intrinsic superoxide dismutase, catalase, and peroxidase-like activities, effectively neutralizing •OH, H2O2, and •OOH radicals. In vitro studies demonstrate PBzymes' ability to mitigate tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in tenocytes and restore cell viability via ROS clearance. In a collagenase-induced rat tendinopathy model, localized PBzyme administration suppressed inflammatory tissue damage, inhibited aberrant differentiation of tendon progenitor cells and promoted collagen fiber realignment achieving a significant increase in biomechanical strength of tissue samples compared to untreated controls. Mechanistically, PBzymes attenuated MAPK signaling activation in M1 macrophages, downregulating pro-inflammatory cytokines (Interleukin-1β and Tumor Necrosis Factor-α) production while enhancing M2 reparative macrophage polarization. Histological and gait analyses of treated rat further confirmed functional recovery, with treated tendons exhibiting near-native collagen architecture and restored locomotor parameters. Comprehensive biosafety evaluations revealed no systemic toxicity that would underscore PBzymes' clinical potential. This work pioneers nanozyme-mediated tendon regeneration, bridging catalytic nanotechnology and immunomodulation to address unmet needs in musculoskeletal therapeutics.