pH-responsive delivery of H_(2) through ammonia borane-loaded mesoporous silica nanoparticles improves recovery after spinal cord injury by moderating oxidative stress and regulating microglial polarization

Imbalance of oxidative and inflammatory regulation is themain contributor to neurofunctional deterioration and failure of rebuilding spared neural networks after spinal cord injury(SCI).As an emerging biosafe strategy for protecting against oxidative and inflammatory damage,hydrogen(H_(2))therapy is a promising approach for improving the microenvironment to allow neural regeneration.However,achieving release of H_(2) at sufficient concentrations specifically into the injured area is critical for the therapeutic effect of H_(2).Thus,we assembled SiO_(2)@mSiO_(2) mesoporous silica nanoparticles and loaded them with ammonia borane(AB),which has abundant capacity and allows controllable release of H_(2) in an acid-dependent manner.The release of H_(2) from AB/SiO_(2)@mSiO_(2) was satisfactory at pH 6.6,which is approximately equal to the microenvironmental acidity after SCI.After AB/SiO_(2)@mSiO_(2) were intrathecally administered to ratmodels of SCI,continuous release of H_(2) fromthese nanoparticles synergistically enhanced neurofunctional recovery,reduced fibrotic scar formation and promoted neural regeneration by suppressing oxidative stress reaction.Furthermore,in the subacute phase of SCI,microglia were markedly polarized toward the M2 phenotype by H_(2) via inhibition of TLR9 expression in astrocytes.In conclusion,H_(2) delivery through AB/SiO_(2)@mSiO_(2) has the potential to efficiently treat SCI through comprehensivemodulation of the oxidative and inflammatory imbalance in themicroenvironment.