Rare earth-doped nanomaterials are known as upconverting nanoparticles (UCNPs) convert low-energy near-infrared light into high-energy visible/ultraviolet light emissions. The anti-Stokes luminescence characteristics of these nanoparticles create special benefits for biomedical applications. Near-infrared light achieves deep tissue penetration while minimizing tissue damage and avoiding biological autofluorescence interference which leads to significantly better imaging sensitivity. UCNPs today serve important functions in bioimaging applications as well as cancer diagnosis and treatment through photothermal and photodynamic therapy combined with drug delivery systems and nanoscale temperature measurements. The promising applications of these materials require thorough safety assessments to understand their potential toxicity and long-term biosafety effects including rare earth element release and nanosize-induced outcomes.

Safety Practices in Medical Applications

Bioimaging: Near-infrared excitation (980 nm) significantly increases the imaging depth to 10-15 mm subcutaneously by reducing tissue autofluorescence and scattering effects, which is particularly suitable for in vivo visualization monitoring of deep solid tumors (such as pancreatic cancer). The core-shell structure design (such as NaYF4 inert shell) can enhance the luminescence efficiency by more than 10 times, while reducing the risk of rare earth ion leakage. Modification with targeted ligands (such as folic acid and hyaluronic acid) can increase the tumor-specific uptake rate by 3-5 times, and reduce the capture of the reticuloendothelial system through polyethylene glycol (PEG) surface functionalization, extending the blood circulation half-life to more than 12 hours.

Integrated cancer diagnosis and treatment: UCNPs can convert 808 nm excitation light into 660 nm visible light through IR-806 dye sensitization, activate photosensitizers (such as Ce6, ZnPc) to produce singlet oxygen (1O2), and the photothermal conversion efficiency mediated by gold nanoshells reaches 70.7°C, realizing the dual mechanism of tumor ablation and vascular embolization. The Nd³⁺ doping system can realize real-time temperature feedback during treatment, improve the local temperature control accuracy to ±0.5°C, and avoid thermal damage to surrounding tissues.

UCNPs coated with mesoporous silica shells (pore size 2-3 nm) release doxorubicin through pH response (tumor microenvironment trigger) or 980 nm light control, with a release efficiency of 80% within 48 hours under acidic conditions, which is 60% lower than the systemic toxicity of traditional chemotherapy. The temperature-sensitive liposome composite system can quickly release drugs when the photothermal temperature rises to 42°C, realizing dual temporal and spatial regulation.

Nanoscale temperature measurement: Based on the temperature dependence of the fluorescence intensity ratio (FIR) of the ²H11/2 and ⁴S3/2 energy levels of Er³⁺, UCNPs can complete real-time temperature measurement in the range of -100°C to 500°C within 0.1 seconds, with a spatial resolution of 50 nm, which is suitable for chip hot spot positioning or tumor ablation boundary monitoring. Multi-parameter temperature-oxygen concentration synchronous sensing can be achieved through Tm³⁺ doping, providing multi-dimensional information for complex biological environments.

How to Choose Safe Upconverting Nanoparticles?

Prefer core-shell structures (such as NaYF₄@NaYF₄) or polyelectrolyte multilayer coated products, whose rare earth ion leakage rate is less than 0.1 ppm/month. The MTT experimental data (IC50>200 μg/mL) and 28-day subacute toxicity report (liver and kidney function index fluctuations <10%) provided by the supplier need to be verified.

Future Challenges and Research Directions

High-throughput screening platform: Use machine learning to optimize the Er³⁺/Tm³⁺ doping ratio (error <0.1 at.%) and predict the Pareto frontier of quantum yield and cytotoxicity.

Integrated diagnosis, treatment and monitoring: Probes based on the FRET mechanism can simultaneously monitor drug release (rhodamine B fluorescence recovery) and reactive oxygen levels (DCFH-DA oxidation) to achieve closed-loop regulation of therapeutic doses. CRISPR-Cas9 functionalized system can trigger gene editing through NIR for drug resistance reversal.