Radially mesoporous silica nanoparticles (RMSNs) with protonated amine functionality are proposed to be a dexamethasone (Dex) carrier that could achieve a sustained anti-inflammatory effect in rheumatoid arthritis (RA). High-capacity loading and a sustained release of target drugs were achieved by radially oriented mesopores and surface functionality. The maximum loading efficiency was confirmed to be about 76 wt%, which is about two times greater than that of representative mesopores silica, SBA-15. In addition, Dex-loaded RMSNs allow a sustained-release profile with about 92% of the loaded Dex for 100 h in vitro, resulting in 2.3-fold better delivery efficiency of Dex than that of the SBA-15 over the same period. In vivo evaluation of the inhibitory effects on inflammation in a RA disease rat model showed that, compared with the control groups, the group treated with Dex-loaded RMSNs sustained significant anti-inflammatory effects and recovery of cartilage over a period of 8 weeks. The in vivo effects were confirmed via micro-computed tomography, bone mineral density measurements, and modified Mankin scoring. The proposed Dex-loaded RMSNs prolonged the life of the in vivo concentrations of therapeutic agents and maximized their effect, which should encourage its application.