Current progress in the controlled synthesis and biomedical applications of ultrasmall (4 nanoparticles

The design and fabrication of rare earth upconversion nanoparticle (UCNP)-based nanomedical platforms have evoked increasing interest. However, their bio-safety is always the most worrisome problem. Most nanoparticles can accumulate in the internal organs, leading to acute toxicity, a long-term inflammatory response, or even fibrosis and cancer. In contrast, ultrasmall (sub-10 nm) nanoparticles have minimal safety risk because they can escape from macrophages, pass biological barriers, and be easily degraded or excreted from the body. In this review, we mainly introduce new progress in preparation strategies, imaging and drug delivery with regards to ultrasmall UCNPs, with an emphasis on rare earth fluorides, NaREF₄. Finally, we discuss the future outlook and challenges relating to ultrasmall UCNPs.