Intracellular small molecule/ion storm from Ca-phytate nanoparticle synergizes neural stem cell therapy and immunomodulation in spinal cord injury.

Neural stem cells (NSCs) transplantation offers a promising therapeutic approach for spinal cord injury (SCI), addressing the challenge of neuron irreparability. However, the uncontrolled differentiation of transplanted NSCs and the inflammatory environment at the injury site limit the efficacy of cell-based treatments. To overcome these obstacles, simultaneously regulating NSCs differentiation and reshaping immune microenvironment is vital for enhancing the effectiveness of cell therapy. In this study, we proposed calcium phytate nanoparticles (Ca-PA NPs) as synergistic regulators capable of promoting neuronal differentiation and regulating the polarization of immune cells. This approach leverages the coordination properties of calcium ions and phytic acid, as well as the decomposition characteristics of calcium phytate. The nanoparticles can be endocytosed by NSCs or microglia, and decomposed in their lysosomes, forming the intracellular small molecule/ion storms. In vitro, NSCs endocytosing Ca-PA NPs predominantly differentiate into neurons, while microglia internalizing the nanoparticles transition from a pro-inflammatory M1 phenotype to a neuroprotective M2 phenotype. Importantly, the animal experiments proved that Ca-PA NPs significantly enhanced functional recovery in SCI mice by synergistically promoting neuronal differentiation of transplanted NSCs and reshaping immuno-microenvironment. These findings open a new route to design nano-regulators for immune microenvironment involved stem cell therapy of SCI.