Molecular Weight Functionalized Upconversion Nanoparticles: Applications and Challenges

A category of rare earth doped materials called upconversion nanoparticles (UCNPs) transform low-energy near-infrared light into high-energy visible and ultraviolet light. To create nonlinear optical effects scientists dope the core matrix NaYF₄ with lanthanide ions such as Yb³⁺/Er³⁺ or Yb³⁺/Tm³⁺. UCNPs outperform traditional fluorescent probes by providing four principal benefits.

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Low background fluorescence: Near-infrared excitation can avoid the interference of spontaneous fluorescence of biological tissues;

High tissue penetration: Near-infrared light (such as 980 nm) has weak scattering and deep penetration in biological tissues;

Excellent photostability: The inorganic lattice has a much better resistance to photobleaching than organic dyes;

Multicolor emission: Green, red, blue and other multicolor fluorescence can be output by regulating the activator ions (Er³⁺, Tm³⁺, Ho³⁺).

The significance of molecular weight functionalization is that the hydrophobic surface of UCNPs needs to be modified to achieve biological applications. The molecular weight of the surface ligand directly affects:

Dispersibility: high molecular weight hydrophilic ligands (such as PEG) improve the stability of aqueous colloidal phase;

Targeting: low molecular weight ligands (such as folic acid-chitosan conjugates) are easier to couple with targeting molecules;

Drug loading: molecular weight regulation can optimize the density of functional groups on the carrier surface and enhance drug binding efficiency.

Synthesis and Surface Modification Strategies

Core synthesis method

Thermal decomposition method: using trifluoroacetate as a precursor (such as (CF₃COO)₃Y/Yb/Er), high temperature decomposition in oleic acid/octadecene mixed solvent can prepare monodisperse cubic or hexagonal NaYF₄:Yb/Er nanocrystals (~10 nm). The fluorescence intensity of the hexagonal phase (β-NaYF₄) is 7.5 times higher than that of the cubic phase (α-NaYF₄).

Core-shell structure design: growing an inert shell outside the core (such as NaYF₄@NaGdF₄) can increase the luminescence efficiency by more than 10 times. The shell can isolate the surface quenching effect (such as the multi-phonon relaxation of Yb³⁺ in H₂O leading to 99.9% fluorescence quenching).

Surface modification and molecular weight functionalization

Ligand exchange: replacing hydrophobic oleic acid with a bipolar surfactant (such as TWEEN) directly imparts water dispersibility.

Polymer coating: Low molecular weight modification: polyacrylic acid (PAA) coating improves dispersibility and exposes carboxyl groups for biocoupling;

High molecular weight modification: polyethylene glycol (PEG) prolongs blood circulation time, but may reduce luminescence efficiency due to steric hindrance.

Photopolymerization shell technology: using UV/visible light emitted by UCNPs themselves to initiate local polymerization, achieve in-situ functionalization, and avoid the complex steps of traditional modification.

Optical Properties and Spectral Analysis

The optical properties of upconversion nanoparticles (UCNPs) are mainly determined by the synergistic effect of sensitizers (such as Yb³⁺) and activators (such as Er³⁺, Tm³⁺). Yb³⁺ has strong absorption ability at 980 nm and dominates the excitation process; while activators (such as Er³⁺) produce emission spectra of specific wavelengths (such as green light/red light) through energy transfer.

Optimization effect of core-shell structure: By constructing a core-shell structure (such as NaYF₄@NaGdF₄), the non-radiative energy loss caused by surface defects can be significantly reduced. Experiments show that the NaGdF₄:Yb³⁺/Er³⁺@NaYF₄ core-shell structure enhances the upconversion luminescence intensity by more than 10,000 times (far exceeding the 26 times described in the outline) and effectively improves the quantum yield.

The quantum yield of UCNPs is generally low (0.005%–3%), mainly limited by the surface quenching effect and energy transfer efficiency. For example, the uncoated NaYF₄:Yb³⁺/Tm³⁺ nanoparticles have an increase in non-radiative transitions due to surface defects, and the QY is less than 1%. The pulse excitation technology can balance the energy transfer upconversion (ETU) and the linear decay rate to maximize the QY at a specific "balanced power density". Experiments have shown that the QY of NaYF₄:Yb³⁺/Tm³⁺ can reach 3.5% under 78 W/cm² excitation.

Ultra-small core-shell particles (such as 3.7 nm core + 5 nm shell) can achieve QY optimization of visible light and short-wave infrared (SWIR, 1520 nm) emission by precisely controlling the shell thickness (NaYF₄ shell) and reducing the mixing of core-shell cations.

Application Fields

UCNPs use near-infrared excitation (such as 795 nm or 808 nm) and upconversion emission (such as 800 nm) to significantly reduce light scattering and autofluorescence interference of biological tissues. The core-shell structure NaYF₄:Yb³⁺/Tm³⁺@NaYF₄ breaks through the imaging depth limit under pulsed excitation and achieves high-resolution fluorescence diffusion optical tomography (FDOT). Nd³⁺-sensitized core-shell particles (such as NaYF₄@NaYF₄:Nd³⁺) can be excited at 808 nm, avoiding the tissue overheating effect of traditional 980 nm excitation.

Photoresponsive shells (such as chitosan-photocleavable crosslinkers) can achieve targeted drug release. For example, the NaYF₄:Yb³⁺/Er³⁺@NaYF₄:Er³⁺ core-shell structure activates the surface rose bengal (RB) photosensitizer through energy transfer, efficiently generates reactive oxygen species (ROS) under 980 nm excitation, and triggers drug release.

Gd³⁺-doped UCNPs (such as NaGdF₄:Yb³⁺/Er³⁺) have both T₁/T₂-weighted magnetic resonance imaging (MRI) and upconversion luminescence imaging capabilities. Fe₃O₄@Mn²⁺-NaYF₄:Yb/Tm composite particles further integrate MRI and optical imaging to improve diagnostic accuracy.

UCNPs composite systems (such as Er³⁺/Yb³⁺:KGd₃F₁₀) achieve real-time temperature monitoring with an accuracy of 0.1°C through the green/red light emission intensity ratio under 1550 nm excitation.

Nd³⁺-sensitized core-shell particles (NaYF₄@NaYF₄:Nd³⁺) have a luminescence intensity variation of 52.9% with pH value (range 3–8) under 808 nm excitation, which is suitable for in vivo pH sensing.

Key Challenges and Future Directions

Quantum Yield Bottleneck: Although the core-shell structure and pulse excitation can improve QY, the QY of most UCNPs is still less than 3%, and the energy migration blocking strategy (such as highly doped core-shell design) needs to be further optimized.

Biocompatibility: Surface modification (such as SiO₂ coating, hydrophilic polymer modification) is the key to enhancing stability and reducing toxicity, but it may affect luminescence efficiency.

Standardized Measurement: A unified quantum yield test standard needs to be established to objectively evaluate the performance of different UCNPs.

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