Near-infrared (NIR) persistent luminescence nanoparticles (PLNPs), possessing unique NIR PL properties, have recently emerged as important materials for a wide variety of applications in chemistry and biology, for which they must endure high-temperature solid-state annealing reactions and subsequent complicated physical post-treatments. Herein, we report on a first direct aqueous-phase chemical synthesis route to NIR PLNPs and present their enhanced in vivo renewable NIR PL. Our method leads to monodisperse PLNPs as small as ca. 8 nm. Such sub-10 nm nanocrystals are readily dispersed and functionalized, and can form stable colloidal solutions in aqueous solution and cell culture medium for biological applications. Under biotissue-penetrable red-light excitation, we found that such nanocrystals possess superior renewable PL photoluminescence in vitro and in vivo compared to their larger counterparts currently made by existing methods. We believe that this solid-state-reaction-free chemical approach overcomes the current key roadblock in regard to PLNP development, and thus will pave the way to broad use of these advanced miniature "luminous pearls" in photonics and biophotonics.