ABSTRACT Particle size plays a pivotal role in defining the optical performance and pharmacokinetic behaviors of lanthanide‐doped upconversion nanoparticles (UCNPs). Yet, the fundamental mechanisms underlying their size‐dependent upconversion luminescence remain elusive and controversial, with unresolved debates on the hierarchical contribution of phonon relaxation, surface quenching, and energy transfer across different size regimes. This review consolidates the evolution of mechanistic understanding—from early phonon relaxation models to the current framework that integrates size‐dependent surface quenching with lanthanide energy transfer processes, and deepens the analysis of conflicting experimental observations and scale‐dependent mechanistic transitions within this integrated model. This refined perspective achieves precise quantitative agreement between theoretical predictions and experimental data, while also identifying critical gaps in explaining extreme nanoscale behavior (<5 nm) and heterogeneous energy transfer in non‐uniform dopant distributions. Recent advances in precise size control have yielded UCNPs with upconversion quantum yields up to 13% (exceeding those of bulk materials), deep‐tissue near‐infrared penetration beyond 3 cm, and tunable size‐mediated clearance pathways. Here, we elaborate on how size modulation directly dictates the translational efficacy of these advances in biological contexts, rather than merely characterizing performance for optimizing Förster resonance energy transfer efficiencies in dye‐sensitized systems and determining photon‐avalanche thresholds that enable super‐resolution imaging—we explore the unresolved trade‐offs between size‐dependent optical performance, biological compatibility, and clinical applicability that limit real‐world deployment. Finally, this review casts a look at future directions centered on addressing these open questions, encompassing sub‐10 nm UCNPs with atomically engineered surfaces to decouple brightness from size, stimuli‐responsive and size‐transformable architectures to resolve in vivo performance dichotomies, and intelligent theranostic nanomedicines that leverage size as a dynamic design variable.
Li et al. (Thu,) studied this question.