The latest research from the Chinese Academy of Sciences provides new ideas for the treatment of spinal cord injury

After spinal cord injury (SCI), nerve survival and tissue regeneration in the damaged site are difficult due to the dynamics and complexity of the injury microenvironment. Among them, oxidative stress and inflammation form multiple positive feedback regulatory signal networks, which dominate after injury and become a marker of the external nerve injury environment. SCI produces reactive oxygen species (ROS) through various cellular and enzyme-mediated signaling pathways. High levels of ROS easily cause oxidative stress, leading to inflammatory events through multiple mechanisms, such as mediating inflammosome activation, targeting degradation of IκB, and promoting the translocation of NF-κB to the nucleus and activating inflammation. With the persistence of immune cells, especially macrophages, by releasing tumor necrosis factor (TNF) and inducing mitochondrial production of ROS. At the same time, this also causes immune cells to secrete more ROS by upregulating the expression of reactive nitrogen, NADPH oxidase and other enzymes. Therefore, strategies that clear reactive oxygen species or inhibit inflammation alone have limited efficacy in treating SCI.

In response to the above problems, the regenerative medicine team of Dai Jianwu and Chen Yanyan of Suzhou Institute of Nanotechnology and Nanobionics, Chinese Academy of Sciences designed an integrated nanoenzyme that binds “nanoflower” Mn3O4 with “pollen” IRF-5SiRNA, which provides a new idea for the combination of antioxidant and anti-inflammatory treatment strategies after spinal cord injury. This strategy mimics the cascade reaction of antioxidant enzymes by vacially engineered nanoenzyme Mn3O4, showing higher substrate affinity and higher maximum reaction rate than natural antioxidant enzymes, which can effectively catalyze the production of oxygen by ROS, reduce oxidative stress, and promote angiogenesis with continuous oxygenation. At the same time, “pollen” IRF-5SiRNA achieves inflammatory macrophage phenotypic reversal by reducing the expression of interferon regulator 5 (IRF-5). The neutrophil membrane is coated with integrated nanoenzymes to further protect and target the delivery of “pollen” IRF-5SiRNA into inflammatory macrophages, thereby effectively reducing the infiltration of inflammatory cells and thus reducing nerve scarring. In rat models of complete spinal cord injury, multifunctional nanoenzymes enhance the regeneration of various neuronal subtypes (motor neurons, interneurons, and sensory neurons) and the restoration of hindlimb motor function. This work provides a new idea and a new means for the treatment of spinal cord injury.

Figure 1. Schematic diagram of the scheme. A) Schematic diagram of IRF-5SiRNA/M@pMn-integrated nanozyme synthesis. B) Schematic diagram of the therapeutic power of the prepared multifunctional nanozyme; It mainly includes macrophage reprogramming and redox regulation. C) Chart showing IRF-5SiRNA/M@pMn recruitment process driven by recruitment factors to target inflammatory macrophages

Figure 2. Preparation and characterization of IRF-5RNA/M@pMn. (A, B)SEM, (C) SAED MODE TEM, (D) TEM and (E, F)HAADF-STEM images. (G) Schematic diagram of IRF-5siRNA nanoparticles. (H) Determination of siRNA-nanocarrier binding capacity using agarose gel electrophoresis. (I) Transmission electron microscopy image of IRF-5RNA/M@pMn. (J) Fourier transform infrared spectroscopy of Mn3O4, pMn and M@pMn nanoparticles. (K) Heat map of membrane protein expression in HL-60 and induced neutrophils. (L) Western blot of CXCR1/2 in M@pMn. The three lanes in the image reflect three replicates. (M) Protein docking simulation of protein docking between CXCR1/2 and CXCL1/2/3. (N) particle size and (O) zeta potential of different nanoparticles (n = 3)

Figure 3. Functional hydrogels induce motor function recovery in long-term animal experiments. A) BBB score of rats from the eighth week post-surgery (n=8). B) Use typical footprint imprints (front paws, blue ink; hind paws, red ink) to check the recovery of hindlimb motor function in rats. C) Representative images of spinal cord anatomy after SCI repair. D) Representative immunofluorescence images after ChAT, Calbindin, and Brn3a staining and quantitative analysis of E) ChAT, F) Calbindin, and G) Brn3a staining (n = 6). H) Tuj1, I) Map2, L) CS56, N) Neuronal differentiation plot of CD31 and its corresponding J), K), M), O), quantitative analysis (n = 3). p) qPCR analysis of markers such as neurons and blood vessels expression (n = 5)

The work was published in Advanced Science under the title Multifunctional Integrated Nanozymes Facilitate Spinal Cord Regeneration by Remodeling the Extrinsic Neural Environment. The first author of the article is Xiong Tiandi, a master student of the Suzhou Institute of Nanotechnology, Chinese Academy of Sciences, and the corresponding authors are Chen Yanyan and Dai Jianwu, researchers of the Suzhou Institute of Nanotechnology, Chinese Academy of Sciences. This work has been supported by the National Natural Science Foundation of China, the National Key Project Grant, the National Key R&D Program, and the Leading Science and Technology Program of the Chinese Academy of Sciences. (Source: Suzhou Institute of Nanotechnology and Nanobionics, Chinese Academy of Sciences)

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