Near-infrared (NIR) persistent-luminescence nanoparticles have emerged as a new class of background-free contrast agents that are promising for in vivo imaging. The next key roadblock is to establish a robust and controllable method for synthesizing monodisperse nanoparticles with high luminescence brightness and long persistent duration. Herein, we report a synthesis strategy involving the coating/etching of the SiO₂ shell to obtain a new class of small NIR highly persistent luminescent ZnGa₂O₄: Cr³⁺, Sn⁴⁺ (ZGOCS) nanoparticles. The optimized ZGOCS nanoparticles have an excellent size distribution of ~15 nm without any agglomeration and an NIR persistent luminescence that is enhanced by a factor of 13.5, owing to the key role of the SiO₂ shell in preventing nanoparticle agglomeration after annealing. The ZGOCS nanoparticles have a signal-to-noise ratio ~3 times higher than that of previously reported ZnGa₂O₄: Cr³⁺ (ZGC-1) nanoparticles as an NIR persistent-luminescence probe for in vivo bioimaging. Moreover, the persistent-luminescence signal from the ZGOCS nanoparticles can be repeatedly re-charged in situ with external excitation by a white lightemitting diode; thus, the nanoparticles are suitable for long-term in vivo imaging applications. Our study suggests an improved strategy for fabricating novel high-performance optical nanoparticles with good biocompatibility.