External and Internal Cultivation Strategy toward Ultra-Bright Lanthanide Nano-Bioprobes

Lanthanide-doped nanobioprobes (LnNBPs) hold substantial promise for biomedical applications. However, their clinical translation remains impeded by inherently low luminescence efficiency due to severe fluorescence quenching arising from lattice and interfacial defects. To address this challenge, we herein propose a simple yet effective external and internal cultivation strategy based on the "whole-body" defect passivation to prepare ultrabright NaGdF₄:Yb/Er@NaYbF₄@NaYF₄ core-shell-shell LnNBPs. By precisely controlling the reaction temperature within a deviation of ±1 °C throughout the entire synthesis process, the "whole-body" lattice and interfacial defects─particularly those localized at the core-shell-shell heterointerfaces─are effectively passivated, resulting in the formation of highly luminescent LnNBPs (∼29 nm) with nearly perfect hexagonal-phase lattice matrix. As such, the as-synthesized NaGdF₄:Yb/Er@NaYbF₄@NaYF₄ LnNBPs exhibit intense upconversion emission under 980 nm xenon-lamp excitation, thereby avoiding undesirable thermal effects associated with conventional high-power laser excitation in diverse LnNBPs. More importantly, a record-high NIR quantum yield of 46.9% is achieved, enabling high-resolution NIR fluorescence imaging of murine vascular networks and bone microstructures with a spatial resolution of approximately 24.3 μm, and thus supporting real-time monitoring of bone disease progression. This study presents a generalizable strategy for constructing highly luminescent LnNBPs with an ideal crystal lattice, offering new opportunities for safe and efficient super-resolution NIR bioimaging in vivo.