Energy‐Supporting Enzyme‐Mimic Nanoscaffold Facilitates Tendon Regeneration Based on a Mitochondrial Protection and Microenvironment Remodeling Strategy

Abstract

Tendon injury is a tricky and prevalent motor system disease, leading to compromised daily activity and disability. Insufficient regenerative capability and dysregulation of immune microenvironment are the leading causes of functional loss. First, this work identifies persistent oxidative stress and mitochondrial impairment in the regional tendon tissues postinjury. Therefore, a smart scaffold incorporating the enzyme mimicry nanoparticle‐ceria nanozyme (CeNPs) into the nanofiber bundle scaffold (NBS@CeO) with porous, anisotropic, and enhanced mechanical properties is designed to innovatively explore a targeted energy‐supporting repair strategy by rescuing mitochondrial function and remodeling the microenvironment favoring endogenous regeneration. The integrated CeNPs scavenge excessive reactive oxygen species (ROS), stabilize the mitochondria membrane potential (ΔΨm), and ATP synthesis of tendon‐derived stem cells (TDSCs) under oxidative stress. In a rat Achilles tendon defect model, NBS@CeO reduces oxidative damage and accelerates structural regeneration of collagen fibers, manifesting as recovering mechanical properties and motor function. Furthermore, NBS@CeO mediates the rebalance of endogenous regenerative signaling and dysregulated immune microenvironment by alleviating senescence and apoptosis of TDSCs, downregulating the secretion of senescence‐associated secretory phenotype (SASP), and inducing macrophage M2 polarization. This innovative strategy highlights the role of NBS@CeO in tendon repair and thus provides a potential therapeutic approach for promoting tendon regeneration.

An Extracellular Vesicle-Cloaked Multifaceted Biocatalyst for Ultrasound-Augmented Tendon Matrix Reconstruction and Immune Microenvironment Regulation

“…28−30 Hydrogen peroxide (H 2 O 2 ) is an essential ROS agent and serves as the source of many other radical species in tendon injury. 5,9 1K,L, S3, and S4). Thus, the Ru doping endowed the nanoparticles with efficient H 2 O 2 scavenging activity (Figure 1J).…”

“…Hydrogen peroxide (H 2 O 2 ) is an essential ROS agent and serves as the source of many other radical species in tendon injury. , CAT can decompose H 2 O 2 into H 2 O and O 2 , which is a crucial kind of enzyme in biological redox equilibrium maintenance. , Consequently, we examined the CAT-mimetic activity of ENs by monitoring the scavenging of H 2 O 2 and the generation of O 2 . − The ENs show a high H 2 O 2 elimination rate with 90.9% decomposition of H 2 O 2 in the first 5 min, whereas the Zn-NCs could not eliminate H 2 O 2 (Figure H). Simultaneously, the evaluation of the generation of O 2 showed that ENs quickly and thoroughly decomposed H 2 O 2 into O 2 and H 2 O (Figure I).…”

“…The healing of tendon injury can be divided into three stages: inflammatory, proliferative, and remodeling . In the initial stage, clinical and experimental studies proved that the level of reactive oxygen species (ROS) constantly increased in acutely injured tendons. , The accumulated ROS can result in tenocyte apoptosis, collagen degradation, suppressed tenogenesis, and M1 macrophage (M1φ) polarization. − The M1φ is a main driver of inflammation and the predominant Mφ phenotype at the onset of tendon injury responsible for secretion of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, and further generation of ROS, which exacerbates the inflammatory cycle and promotes a proinflammatory immune microenvironment. , The proliferative stage is characterized by predominant type-III collagen (COLIII) rather than type-I collagen (COLI) deposition directed by recruited fibroblasts that provide a rapid “patch” to the injured area . Furthermore, the ROS-triggered oxidative stress impairment and inflammation can increase the COLIII/COLI ratio to produce tendon adhesion and fibrosis .…”

Engineered Metallic Ion-Based Hydrogel for Tendon-Bone Reconstruction

“…Rotator cuff injury is a common disease in sports medicine, which has a great impact on shoulder joint function . Blood supply interruption after tendon injury results in a difficult recovery process due to the low vascularity of the tissue. , Immune microenvironments are also critical to the formation of tissues in osteoimmunology . It is beneficial for tissue healing when macrophages polarize to the M2 phenotype. , In the case of tendon injury, the bone defect may cause the refixed tendon-bone enthesis to retear again. , As a result, the key for rotator cuff tissue repair is to promote the regeneration of the tendon vascular tissue, regulate the immune microenvironment, and strengthen the stability of the tendon-bone enthesis.…”

“…2,3 Immune microenvironments are also critical to the formation of tissues in osteoimmunology. 4 It is beneficial for tissue healing when macrophages polarize to the M2 phenotype. 5,6 In the case of tendon injury, the bone defect may cause the refixed tendon-bone enthesis to retear again.…”