Lanthanide ions facilitate efficient conversion from long-wavelength near-infrared light (980 nm or 808 nm) to short-wavelength visible/ultraviolet light (Upconverting luminescence) through multiphoton absorption and energy transfer enabled by their stepped electronic energy level structure. The property of this technology overcomes conventional fluorescent materials' Stokes shift limits while eliminating tissue autofluorescence interference and improving light penetration depth. Within biomedical applications, Upconverting nanoparticles (UCNPs) demonstrate minimal phototoxicity alongside exceptional photostability and deep penetration of tissues which positions them as superior replacements for existing organic dyes and quantum dots. Near-infrared excitation achieves high-resolution imaging of living tumors and blood vessels by reducing tissue scattering.
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Optical Properties of Lanthanide-doped Upconverting Nanoparticles
Lanthanide-doped Upconverting nanoparticles (UCNPs) derive their optical properties from both their unique energy transfer mechanism and their optimized structural engineering. Near-infrared photon absorption by sensitizers such as Yb³⁺ triggers multi-step energy transfer that activates luminescent centers like Er³⁺, Tm³⁺ or Ho³⁺ which results in Upconverting emission from low-energy near-infrared light to high-energy visible or ultraviolet light. Physical isolation of surface defects and solvent molecules within the core-shell structure decreases non-radiative transition probability to less than one-tenth of what it was in the original structure which boosts quantum yield to commercial standards. For example, the quantum yield of NaYF₄: Core-shell particles containing Yb and Er have achieved quantum yields as high as 1%, showing a tenfold improvement over shell-free materials. Research indicates a 15% improvement in luminescence efficiency for each 1 nm thicker shell and both NaYF₄ and CaF₂ shells can deliver approximately 40 times the luminescence enhancement.
Through ion doping engineering, UCNPs can achieve full spectrum coverage: Eu³⁺ produces characteristic red light at 613 nm, and Tb³⁺ emits green light at 545 nm. The more innovative composite structure design extends the emission wavelength to the near-infrared II region (1000-1700 nm) through the fluorescence resonance energy transfer (FRET) mechanism, significantly improving the tissue penetration depth. The dye sensitization strategy extends the absorption range to the 800 nm band through the molecular antenna effect, achieving an 87-fold Upconverting luminescence enhancement in the Li(Gd,Y)F₄:Yb,Tm@LiYF₄:Nd,Yb system, while avoiding the problem of tissue overheating caused by traditional 980 nm excitation.
Progress in Synthesis and Functionalization of Lanthanide-doped Upconverting Nanoparticles
In terms of synthesis methods, the thermal decomposition method can prepare hexagonal NaYF₄ nanocrystals with excellent monodispersity (PDI<0.1), while the improved hydrothermal method enables mass production to reach the gram level/batch, and the water dispersibility is increased by more than 3 times. The combined screening technology successfully compressed the emission linewidth to <15 nm when the Yb³⁺/Er³⁺ ratio was optimized to 20:2 through high-throughput experiments, laying the foundation for multiplex detection. In terms of surface functionalization, zwitterionic polymer modification extends the stability of UCNPs in serum to more than 72 hours, while aminosilanization treatment increases the antibody coupling efficiency to 95%, such as the targeted enrichment coefficient of anti-EGFR antibody-modified UCNPs in pancreatic cancer models of 8.7.
Innovative application expansion
In the biomedical field, ultra-small NaYbF₄:Tm³⁺ nanocrystals (7-10 nm) achieve a breakthrough in deep tissue imaging resolution to the subcellular level through the near-infrared-near-infrared conversion mechanism. The Mn²⁺ co-doping system not only increases the red light emission ratio of Er³⁺ to 82%, but also can be used as a pH-responsive drug carrier to achieve the integration of doxorubicin controlled release and diagnosis and treatment. More cutting-edge is that the long-lived excited state (millisecond level) of UCNPs combined with plasma enhancement technology enables single-particle detection sensitivity to reach the zeptomolar level, providing a low phototoxicity (<5 mW/cm²) solution for super-resolution microscopy (such as STED). In addition, by constructing a NaYF₄@Au core-shell structure and utilizing the localized surface plasmon resonance effect, the Upconverting luminescence intensity can be enhanced by 45 times, opening up a new path for the development of miniaturized optoelectronic devices.
Biomedical Imaging Applications of Lanthanide-doped Upconverting Nanoparticles
Deep tissue imaging
Near-infrared excitation (such as 808 nm or 975 nm) significantly increases the penetration depth to the millimeter level by reducing light scattering and absorption in biological tissues. For example, Tm³⁺/Yb³⁺-doped sodium fluoride nanocrystals (20-30 nm) can emit ~800 nm near-infrared light under 975 nm excitation, achieving high-contrast imaging in mice without significant cytotoxicity. CaF₂:Tm,Yb nanoparticles have a penetration depth of nearly 2 mm at low power density, while the core-shell structure (α-NaYbF₄:Tm)@CaF₂ can even penetrate 16 mm of muscle and bone tissue, providing a technical basis for single-particle analysis of tumor microenvironment heterogeneity. In addition, by exciting UCNPs with a 980 nm annular beam and combining nonlinear saturated emission characteristics, 60 nm super-resolution imaging (NIRES nano-imaging technology) can be achieved in deep tissues, significantly improving the accuracy of tumor boundary identification.
Multimodal imaging
UCNPs can integrate multiple imaging modes by doping or compounding functional components. For example, the NaGdF₄:Yb,Er@NaGdF₄ core-shell structure combines Upconverting luminescence (UCL) and T1-weighted magnetic resonance imaging (MRI) functions, and its longitudinal relaxation rate (r₁) reaches 5.60 s⁻¹·mM⁻¹, which is better than clinical gadolinium-based contrast agents. Similarly, 18F-labeled NaYF₄:Yb,Er,Gd nanoparticles can simultaneously support positron emission tomography (PET), MRI, and UCL imaging, achieving multi-scale diagnosis from cells to living bodies, with complementary advantages in sensitivity and spatial resolution. This multimodal design not only improves diagnostic accuracy, but also allows real-time monitoring of dynamic changes in tumors during treatment, such as synchronous imaging of cell apoptosis during the release of photoactivated platinum prodrugs.
Lanthanide-doped Upconverting Nanoparticles Therapeutic Applications
UCNPs can convert near-infrared light into ultraviolet/visible light, activating photosensitizers (such as Ce6) to produce reactive oxygen species (ROS). For example, NaYF₄:Yb,Tm@SiO₂ nanoparticles emit 365 nm ultraviolet light under 980 nm excitation to trigger zinc phthalocyanine (ZnPc) to generate singlet oxygen, and the apoptosis induction efficiency of drug-resistant ovarian cancer cells is 80%. To enhance the photothermal conversion efficiency, the Au@UCNPs core-shell structure can be heated to 50°C under 4 W/cm² laser to directly kill cancer cells, while the surface plasmon resonance effect of the gold shell is used to enhance near-infrared absorption.
Chemotherapeutic drugs (such as gemcitabine) can be loaded by coating UCNPs with mesoporous silica or polydopamine. Near-infrared light-triggered drug release increases the local concentration of tumors by 3-5 times, while significantly reducing systemic toxicity. For example, folic acid-modified UCNPs can target tumor cells with high expression of folate receptors, and combine MRI/UCL dual-mode imaging to track drug distribution in real time. In addition, pH-responsive coatings (such as polyethylene glycol-polylactic acid) can selectively release doxorubicin in the slightly acidic environment of tumors to enhance therapeutic specificity.
Integration of Diagnosis and Treatment and Clinical Transformation
UCNPs can be used as both imaging probes and therapeutic carriers. In a pancreatic cancer model, UCNPs targeting EGFR combined with photodynamic therapy (PDT) reduced tumor volume by 70% and prolonged mouse survival by 2 times. The latest preclinical studies showed that intraoperative real-time imaging can accurately guide tumor resection boundaries (error < 0.5 mm), and simultaneously implement PDT to reduce postoperative recurrence. In addition, 18F-labeled UCNPs can dynamically evaluate drug metabolism and efficacy through PET/MRI multimodal imaging, providing a basis for personalized treatment.
Lanthanide-doped Upconverting nanoparticles are reshaping the technical boundaries of biomedical imaging and treatment with their unique optical properties and programmable functions. In the future, through intelligent response design (such as pH or enzyme triggering) and clinical transformation optimization, UCNPs are expected to become one of the core tools of precision medicine.
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