A new type of core–shell upconversion nanoparticles which can be effectively excited at 795 nm has been designed and synthesized through spatially confined doping of neodymium (Nd3+) ions. The use of Nd3+ ions as sensitizers facilitates the energy transfer and photon upconversion of a series of lanthanide activators (Er3+, Tm3+, and Ho3+) at a biocompatible excitation wavelength (795 nm) and also significantly minimizes the overheating problem associated with conventional 980 nm excitation. Importantly, the core–shell design enabled high-concentration doping of Nd3+ (∼20 mol %) in the shell layer and thus markedly enhanced the upconversion emission from the activators, providing highly attractive luminescent biomarkers for bioimaging without autofluorescence and concern of overheating.