Ultrasmall Luminescent Metal Nanoparticles: Surface Engineering Strategies for Biological Targeting and Imaging

In the past decade, ultrasmall luminescent metal nanoparticles (ULMNPs, d < 3 nm) have achieved rapid progress in addressing many challenges in the healthcare field because of their excellent physicochemical properties and biological behaviors. With the sharp shrinking size of large plasmonic metal nanoparticles (PMNPs), the contributions from the surface characteristics increase significantly, which brings both opportunities and challenges in the application‐driven surface engineering of ULMNPs toward advanced biological applications. Here, the systematic advancements in the biological applications of ULMNPs from bioimaging to theranostics are summarized with emphasis on the versatile surface engineering strategies in the regulation of biological targeting and imaging performance. The efforts in the surface functionalization strategies of ULMNPs for enhanced disease targeting abilities are first discussed. Thereafter, self‐assembly strategies of ULMNPs for fabricating multifunctional nanostructures for multimodal imaging and nanomedicine are discussed. Further, surface engineering strategies of ratiometric ULMNPs to enhance the imaging stability to address the imaging challenges in complicated bioenvironments are summarized. Finally, the phototoxicity of ULMNPs and future perspectives are also reviewed, which are expected to provide a fundamental understanding of the physicochemical properties and biological behaviors of ULMNPs to accelerate their future clinical applications in healthcare.