Formulation of pH-responsive PEGylated nanoparticles with high drug loading capacity and programmable drug release for enhanced antibacterial activity

In the current global crisis of antibiotic resistance,delivery systems are emerging to combat resistant bacteria in a more efficient manner.Despite the significant advances of antibiotic nanocarriers,many challenges like poor biocompatibility,premature drug release,suboptimal targeting to infection sites and short blood circulation time are still challenging.To achieve targeted drug delivery and enhance antibacterial activity,here we reported a kind of pH-responsive nanoparticles by simply self-assembly of an amphiphilic poly(ethylene glycol)-Schiff-vancomycin(PEG-Schiff-Van)prodrug and free Van in one drug delivery system.The acid-liable Schiff base furnished the PEG-Schiff-Van@Van with good storage stability in the neutral environment and susceptible disassembly in response to faintly acidic condition.Notably,on account of the combination of physical encapsulation and chemical conjugation of vancomycin,these nanocarriers with favorable biocompatibility and high drug loading capacity displayed a programmed drug release behavior,which was capable of rapidly reaching high drug concentration to effectively kill the bacteria at an early period and continuously exerting an bacteria-sensitive effect whenever needed over a long period.In addition,more Schiff-base moieties within the PEG-Schiff-Van@Van nanocarriers may also make great contributions on promoting the antimicrobial activity.Using this strategy,this system was designed to have programmable structural destabilization and sequential drug release due to changes in pH that were synonymous with bacterial infection sites,thereby presenting prominent antibacterial therapy both in vitro and in vivo.This work represents a synergistic strategy on offering important guidance to rational design of multifunctional antimicrobial vehicles,which would be a promising class of antimicrobial materials for potential clinical translation.

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.