Immunomodulatory Layered Double Hydroxide Nanoparticles Enable Neurogenesis by Targeting Transforming Growth Factor-β Receptor 2

TLDR

Immune microenvironment amelioration by functional biomaterials is a promising strategy for spinal cord injury recovery. The study aimed to evaluate the neural regeneration and immunoregulation effects of Mg/Al layered double hydroxide nanoparticles in completely transected and excised mice. The authors used Mg/Al-LDH nanoparticles to investigate immune‑related mechanisms in this SCI model. Mg/Al-LDH accelerated neural stem cell migration, differentiation, calcium‑channel activation, and action‑potential generation, improved behavioral and electrophysiological outcomes, increased endogenous NSCs and neurons at lesion sites, identified TGFBR2 as a key mediator of anti‑inflammatory and regenerative effects, and showed that LDH‑loaded NT3 further enhanced recovery, with M1/M2 macrophage shifts reversed by a TGFBR2 inhibitor.

Abstract

Immune microenvironment amelioration and reconstruction by functional biomaterials has become a promising strategy for spinal cord injury (SCI) recovery. In this study, we evaluated the neural regeneration and immunoregulation functions of Mg/Al layered double hydroxide (Mg/Al-LDH) nanoparticles in completely transected and excised mice and revealed the immune-related mechanisms. LDH achieved significant performance in accelerating neural stem cells (NSCs) migration, neural differentiation, L-Ca2+ channel activation, and inducible action potential generation. In vivo, the behavioral and electrophysiological performance of SCI mice was significantly improved by LDH implantation, with BrdU+ endogenous NSCs and neurons clearly observed in the lesion sites. According to RNA-seq and ingenuity pathway analysis, transforming growth factor-β receptor 2 (TGFBR2) is the key gene through which LDH inhibits inflammatory responses and accelerates neural regeneration. Significant colocalization of TGFBR2 and LDH was found on the cell membranes of NSCs both in vitro and in vivo, and LDH increased the expression of TGF-β2 in NSCs and activated the proliferation of precursor neural cells. LDH decreased the expression of M1 markers and increased the expression of M2 markers in both microglia and bone marrow-derived macrophages, and these effects were reversed by a TGFBR2 inhibitor. In addition, as a carrier, LDH loaded with NT3 exhibited better recovery effects with regard to the basso mouse scale score, motor evoked potential performance, and regenerated neural cell numbers than LDH itself. Thus, we have developed Mg/Al-LDH that can be used to construct a suitable immune microenvironment for SCI recovery and have revealed the targeted receptor.