Optogenetics precisely regulates neuronal activity through photosensitive proteins, but its dependence on visible light leads to low tissue penetration depth and high scattering rate, limiting its application in deep tissues. Upconversion nanoparticles (UCNPs) convert deep-penetrating near-infrared light (NIR, 980nm) into visible/ultraviolet light through a nonlinear optical process, activating photosensitive proteins and solving the penetration bottleneck.
The unique advantages of UCNPs include:
High tissue penetration: NIR excitation light has low scattering and low absorption in biological tissues, and the penetration depth can reach the centimeter level;
Low phototoxicity: Avoid direct damage to cells by ultraviolet light;
Precise spatiotemporal control: By regulating the position and time of light illumination, neural stimulation at the single-cell level can be achieved.
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Design and Spectral Optimization of UCNPs
UCNPs often use a core-shell structure (such as NaYF4:Yb/Tm@NaYF4) to reduce energy quenching caused by surface defects. Among them: the sensitizer ytterbium ion (Yb3+) is doped in the core layer, and its large absorption cross section (~980nm) efficiently captures NIR photons, and achieves upconversion luminescence through energy transfer to the activator thulium ion (Tm3+) or erbium ion (Er3+); the inert shell layer (such as NaYF4) wraps the core layer to suppress the non-radiative energy loss caused by lattice vibration and improve the quantum yield.
By adjusting the doped ions (such as Tm3+ emitting blue light 450-480nm), the output spectrum of UCNPs is matched ~470nm. Experiments have confirmed that the blue light generated by NaYF4:Yb/Tm UCNPs under 980nm excitation can effectively activate neuronal; quasi-continuous wave (quasi-CW) excitation (such as pulsed NIR laser) is used to reduce the risk of photothermal effect and improve biocompatibility. Conventional high-intensity continuous wave lasers are prone to overheating of tissues, while pulse modulation can maintain efficient upconversion at low average power.
UCNPs are given targeting properties through ligand modification (such as polyethylene glycol, antibodies, and peptide chains). For example, coupling peptide chains targeting neuronal receptors to the surface of UCNPs can achieve cell membrane-specific localization; SiO2-coated UCNPs (such as NaYF4:Yb/Tm@SiO2) can be inserted into the cell membrane through hydrophobic interaction, locally releasing ultraviolet/blue light to activate membrane proteins, and avoiding signal delays caused by endocytosis. Electron microscopy images directly confirm that UCNPs are localized on the cell membrane.
Targeting and Cell Membrane Specificity Strategies
(1) Surface functionalization
Antibody-antigen binding: NeutrAvidin-biotin system or V5 antibody is used to achieve specific binding of UCNPs to cell membrane surface proteins to enhance targeting accuracy. For example, after UCNPs are surface-modified with StrepTag, they can bind to Streptavidin on the cell membrane to achieve precise positioning.
Polymer coating: UCNPs are coated with materials such as polyamide (PAMAM) dendrimers to significantly improve their water solubility, biocompatibility and cell membrane affinity, and reduce nonspecific adsorption. Polyethylene glycol ligands (PEG) further reduce immunogenicity and prolong in vivo circulation time.
(2) Local positioning technology
Implantable stents: Polymer stents such as polymethyl methacrylate (PMMA) can achieve long-term residence of UCNPs in target brain areas (such as hippocampus and ventral tegmental area), reduce diffusion and maintain stable stimulation.
Targeted delivery system: UCNPs are guided to specific neuronal subpopulations through molecular markers (such as folic acid, transferrin, and aptamers). For example, folic acid-modified UCNPs can target folate receptors overexpressed by cancer cells, while aptamer modification enables neuronal subtype-specific binding.
Application Cases of UCNPs in Optogenetics
(1) Deep brain stimulation
Dopamine neuron regulation: NaYF4:Yb/Tm@SiO2 UCNPs were injected into the ventral tegmental area (VTA) of mice. After near-infrared light (NIR) excitation, successfully regulating dopamine neuron activity and affecting behavioral memory. c-Fos immunofluorescence confirmed neuronal activation, and the penetration depth reached 2mm.
Epilepsy inhibition: UCNPs target hippocampal excitatory neurons, and after NIR excitation, abnormal discharges are inhibited, significantly reducing the frequency of epileptic seizures, providing a non-invasive treatment for deep brain diseases.
(2) Singlet oxygen generation and photodynamic synergy
Photodynamic therapy (PDT): UCNPs are combined with photosensitizers (such as Rose Bengal RB, Ce6) to generate singlet oxygen (1O2) through an energy transfer mechanism, achieving NIR-triggered cancer cell apoptosis. For example, nuclear-targeted UCNP/RB@mSiO2-NH2 nanoparticles efficiently kill tumor cells under multiple NIR irradiation.
Gene-photodynamic synergy: UCNPs loaded with siRNA synchronously release therapeutic nucleic acids and generate reactive oxygen species under NIR excitation, and enhance the anti-tumor effect through RNA interference (RNAi) and PDT synergistically.
(3) Model organism research
Nematode neuron manipulation: In Caenorhabditis elegans (C. elegans), multispectral UCNPs are excited by 808nm NIR and synchronously emit blue light (450–470nm) and red light (590–610nm), respectively activating miniSOG on the mitochondrial membrane (generating reactive oxygen species) on the cell membrane (increasing Ca2+). The two work together to quickly damage the target neurons, accurately inhibit backward movement, and remain effective after penetrating chicken breast tissue.
Biosafety: The technology has no significant effect on nematode development, growth, and egg laying, proving its high biocompatibility.
Innovation of UCNPs
Scientific basis for the targeting strategy: Surface functionalization (antibodies/polymers) and local positioning (scaffolds/molecular markers) solve the problems of cell membrane affinity and tissue retention, respectively, forming a complete chain of delivery-positioning-activation.
Breakthrough in deep brain stimulation: UCNPs combine the advantages of NIR penetration depth with optogenetics specificity to overcome the trauma limitations of traditional fiber optic implants.
Synergistic therapeutic mechanism: The linkage between singlet oxygen generation and gene regulation expands the application dimension of UCNPs in the treatment of cancer and neurological diseases.
Cross-species applicability: From mammals (mice) to invertebrate model organisms (nematodes), the universality and safety of the technology are verified.
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