Robust and Multifunctional Nanoparticles Assembled from Natural Polyphenols and Metformin for Efficient Spinal Cord Regeneration

The treatment of spinal cord injury (SCI) remains unsatisfactory owing to the complex pathophysiological microenvironments at the injury site and the limited regenerative potential of the central nervous system. Metformin has been proven in clinical and animal experiments to repair damaged structures and functions by promoting endogenous neurogenesis. However, in the early stage of acute SCI, the adverse pathophysiological microenvironment of the injury sites, such as reactive oxygen species and inflammatory factor storm, can prevent the activation of endogenous neural stem cells (NSCs) and the differentiation of NSCs into neurons, decreasing the whole repair effect. To address those issues, a series of robust and multifunctional natural polyphenol-metformin nanoparticles (polyphenol-Met NPs) were fabricated with pH-responsiveness and excellent antioxidative capacities. The resulting NPs possessed several favorable advantages: First, the NPs were composed of active ingredients with different biological properties, without the need for carriers; second, the pH-responsiveness feature could allow targeted drug delivery at the injured site; more importantly, NPs enabled drugs with different performances to exhibit strong synergistic effects. The results demonstrated that the improved microenvironment by natural polyphenols boosted the differentiation of activated NSCs into neurons and oligodendrocytes, which could efficiently repair the injured nerve structures and enhance the functional recovery of the SCI rats. This work highlighted the design and fabrication of robust and multifunctional NPs for SCI treatment via efficient microenvironmental regulation and targeted NSCs activation.