Engineering Nanozymes for Tumor Therapy via Ferroptosis Self-Amplification.

Ferroptosis induction is an emerging strategy for tumor therapy. Reactive oxygen species (ROS) can induce ferroptosis but are easily consumed by overexpressed glutathione (GSH) in tumor cells. Therefore, achieving a large amount of ROS production in tumor cells without being consumed is key to efficiently inducing ferroptosis. In this study, a self-amplifying ferroptosis-inducing therapeutic agent, Pd@CeO2-Fe-Co-WZB117-DSPE-PEG-FA (PCDWD), is designed for tumor therapy. PCDWD exhibits excellent multi-enzyme activities due to the loading of Fe-Co dual atoms with abundant active sites, including peroxidase-like enzymes, catalase-like enzymes, and glutathione oxidases (GSHOx), which undergo catalytic reactions in the tumor microenvironment to produce ROS, thereby inducing ferroptosis. Furthermore, PCDWD can also deplete GSH in tumor cells, thus reducing the consumption of ROS by GSH and inhibiting the expression of GSH peroxidase 4. Moreover, the photothermal effect of PCDWD can not only directly kill tumor cells but also further enhance its own enzyme activities, consequently promoting ferroptosis in tumor cells. In addition, WZB117 can reduce the expression of heat shock protein 90 by inhibiting glucose transport, thereby reducing the thermal resistance of tumor cells and further improving the therapeutic effect. Finally, X-ray computed tomography imaging of PCDWD guides it to achieve efficient tumor therapy.

Biodegradable Monometallic Aluminum as a Biotuner for Tumor Pyroptosis.

Pyroptosis is an effective anti-tumor strategy. However, monometallic pyroptosis biotuners have not been explored until now. Here, we discover for the first time that biodegradable monometallic Al can act as a pyroptosis biotuner for tumor therapy. pH-sensitive Al nanoparticles (Al@P) are obtained by equipping polyethylene glycol-b-(poly(methyl methacrylate)-co-poly(4-vinylpyridine), which can exert their effect at the tumor site without affecting normal cells. The H2 and Al3+ release by Al@P in the acidic environment of tumors disrupts the redox balance and ionic homeostasis in tumor cells, thus generating large amounts of reactive oxygen species (ROS), leading to caspase-1 activation, gasdermin D cleavage, and IL-1ß/LDH release, which induces canonical pyroptotic death. Meanwhile, the prodrug Doxorubicin (Pro-DOX) is successfully loaded onto Al@P (Al@P-P) and can be activated by ROS to release DOX in the tumor cells, thus further improving the tumor-killing efficiency. Ultimately, Al@P-P is degradable and exhibits efficient tumor inhibition.

Achieving Orthogonal Upconversion Luminescence of a Single Lanthanide Ion in Crystals for Optical Encryption.

Optical encryption shows great potential in meeting the growing demand for advanced anti-counterfeiting in the information age. The development of upconversion luminescence (UCL) materials capable of emitting different colors of light in response to different external stimuli holds great promise in this field. However, the effective realization of multicolor UCL materials usually requires complex structural designs. In this work, orthogonal UCL is achieved in crystals with a simple structure simply by introducing modulator Tm3+ ions to control the photon transition processes between different energy levels of activator Er3+ ions. The obtained crystals emit red and green UCL when excited by 980 nm and 808 nm lasers, respectively. The orthogonal excitation-emission properties of crystals are shown to be very suitable for high-level optical encryption, which is important for information security and anti-counterfeiting. This work provides an effective strategy for obtaining orthogonal UCL in simple structural materials, which will encourage researchers to further explore novel orthogonal UCL materials and their applications, and has important implications for the development of the frontier photonic upconversion fields.

Near-Infrared-Responsive Rare Earth Nanoparticles for Optical Imaging and Wireless Phototherapy.

Near-infrared (NIR) light is well-suited for the optical imaging and wireless phototherapy of malignant diseases because of its deep tissue penetration, low autofluorescence, weak tissue scattering, and non-invasiveness. Rare earth nanoparticles (RENPs) are promising NIR-responsive materials, owing to their excellent physical and chemical properties. The 4f electron subshell of lanthanides, the main group of rare earth elements, has rich energy-level structures. This facilitates broad-spectrum light-to-light conversion and the conversion of light to other forms of energy, such as thermal and chemical energies. In addition, the abundant loadable and modifiable sites on the surface offer favorable conditions for the functional expansion of RENPs. In this review, the authors systematically discuss the main processes and mechanisms underlying the response of RENPs to NIR light and summarize recent advances in their applications in optical imaging, photothermal therapy, photodynamic therapy, photoimmunotherapy, optogenetics, and light-responsive drug release. Finally, the challenges and opportunities for the application of RENPs in optical imaging and wireless phototherapy under NIR activation are considered.

Wireless Photoactivated Targeted Nanosystem for Oncotherapy Via Synergistic Effects of Hyperthermia/Redox Stress Amplification/GSK-3ß Activity Inhibition.

Highly soluble salts and gas mediated therapies are emerging antitumor strategies. However, the therapeutic efficacy remains restricted by difficulty in delivering them to the tumor site and poorly controlled release in deep tissues. Here, an intelligent wireless photoactivated targeted nanosystem is designed for delivering LiCl and H2 to tumors for therapy. LiCl causes cell death by inhibiting the activity of GSK-3ß. H2 selectively interacts with reactive oxygen species in the tumor, leading to redox stress, which induces apoptosis. The significant heat generated by the nanosystem not only kills tumor cells but also accelerates the dissolution of LiCl and the release of H2. The rapid dissolution of LiCl leads to a surge in intracellular osmotic pressure, which further intensifies the redox stress response and enhances the efficiency of therapy. The nanosystem shows efficient tumor therapeutic capability via synergistic effects of hyperthermia/redox stress amplification/GSK-3ß activity inhibition.

New Strategy: Molten Salt-Assisted Synthesis to Enhance Lanthanide Upconversion Luminescence.

Lanthanide-doped upconversion luminescent materials (LUCMs) have attracted much attention in diverse practical applications because of their superior features. However, the relatively weak luminescence intensity and low efficiency of LUCMs are the bottleneck problems that seriously limit their development. Unfortunately, most of the current major strategies of luminescence enhancement have some inherent shortcomings in their implementation. Here, a new and simple strategy of molten salt-assisted synthesis is proposed to enhance lanthanide upconversion luminescence for the first time. As a proof-of-concept, a series of rare earth oxides with obvious luminescence enhancement are prepared by a one-step method, utilizing molten NaCl as the high-temperature reaction media and rare earth chlorides as the precursors. The enhancement factors at different reaction temperatures are systematically investigated by taking Yb3+ /Er3+ co-doped Y2 O3 as an example, which can be enhanced up to more than six times. In addition, the molten salts are extended to all alkali chlorides, indicating that it is a universal strategy. Finally, the potential application of obtained UCL materials is demonstrated in near-infrared excited upconversion white light-emitting diodes (WLEDs) and other monochromatic LEDs.

Multifunctional Superparticles for Magnetically Targeted NIR-II Imaging and Photodynamic Therapy.

Theranostics, the combination of diagnostics and therapies, has been considered as a promising strategy for clinical cancer treatment. Nonetheless, building a smart theranostic system with multifunction for different on-demand applications still remains elusive. Herein, an easy and user-friendly microemulsion based method is developed to modularly assemble upconversion nanoparticles (UCNPs) and Fe3 O4 nanoparticles together, forming multifunctional UCNPs/Fe3 O4 superparticles with highly integrated functionalities including the 808 nm excitation for real-time NIR-II imaging, magnetic targeting, and the upconversion luminescence upon 980 nm excitation for on-demand photodynamic therapy (PDT). With a magnet placed nearby the tumor, in vivo NIR-II imaging uncovers that superparticles tend to migrate toward the tumor and exhibit intense tumor accumulation, ≈6 folds higher than that without magnetic targeting 2 h after intravenous injection. NIR laser irradiation is then used to trigger PDT, obtaining an outstanding tumor elimination under magnetic tumor targeting, which shows a high potential to be applied in targeted cancer theranostics.

Hollow nanoparticles synthesized via Ostwald ripening and their upconversion luminescence-mediated Boltzmann thermometry over a wide temperature range.

Upconversion nanoparticles (UCNPs) with hollow structures exhibit many fascinating optical properties due to their special morphology. However, there are few reports on the exploration of hollow UCNPs and their optical applications, mainly because of the difficulty in constructing hollow structures by conventional methods. Here, we report a one-step template-free method to synthesize NaBiF4:Yb,Er (NBFYE) hollow UCNPs via Ostwald ripening under solvothermal conditions. Moreover, we also elucidate the possible formation mechanism of hollow nanoparticles (HNPs) by studying the growth process of nanoparticles in detail. By changing the contents of polyacrylic acid and H2O in the reaction system, the central cavity size of NBFYE nanoparticles can be adjusted. Benefiting from the structural characteristics of large internal surface area and high surface permeability, NBFYE HNPs exhibit excellent luminescence properties under 980 nm near-infrared irradiation. Importantly, NBFYE hollow UCNPs can act as self-referenced ratiometric luminescent thermometers under 980 nm laser irradiation, which are effective over a wide temperature range from 223 K to 548 K and have a maximum sensitivity value of 0.0065 K-1 at 514 K. Our work clearly demonstrates a novel method for synthesizing HNPs and develops their applications, which provides a new idea for constructing hollow structure UCNPs and will also encourage researchers to further explore the optical applications of hollow UCNPs.

Full shell coating or cation exchange enhances luminescence.

Core-shell structure is routinely used for enhancing luminescence of optical nanoparticles, where the luminescent core is passivated by an inert shell. It has been intuitively accepted that the luminescence would gradually enhance with the coverage of inert shell. Here we report an "off-on" effect at the interface of core-shell upconversion nanoparticles, i.e., regardless of the shell coverage, the luminescence is not much enhanced unless the core is completely encapsulated. This effect indicates that full shell coating on the luminescent core is critical to significantly enhance luminescence, which is usually neglected. Inspired by this observation, a cation exchange approach is used to block the energy transfer between core nanoparticle and surface quenchers. We find that the luminescent core exhibits enhanced luminescence after cation exchange creates an effective shell region. These findings are believed to provide a better understanding of the interfacial energy dynamics and subsequent luminescence changes.

Decoration of upconversion nanocrystals with metal sulfide quantum dots by a universal in situ controlled growth strategy.

Conjugating transition-metal sulfide quantum dots and upconversion nanocrystals (UCNCs) has aroused widespread concern due to enhanced physical and chemical properties in contrast to only their simple sum. However, the synthesis of such hybrid nanoparticles by a universal in situ growth strategy has been scarcely reported so far. Herein, we developed a facile approach to functionalize NaYF4:Yb/Er with chitosan (NaYF4:Yb/Er@CS), which not only could improve the hydrophilicity of NaYF4:Yb/Er, but also can form stable chelates with transition-metal ions. Then, ultrasmall metal sulfide (Mn+S, M = Ag, Cu, Cd) quantum dots (QDs) can be conjugated homogeneously on the surface of NaYF4:Yb/Er@CS. Taking Ag2S as an example, the growth behavior of Ag2S QDs on the surface of NaYF4:Yb/Er@CS was studied specifically. The influence of the Ag : Y ratio, S : Ag ratio, pH value, reaction time and reaction temperature on the growth behavior of Ag2S on the surface of NaYF4:Yb/Er@CS was investigated systematically. Meanwhile, this innovative strategy is also suitable for the growth of ultrasmall QDs in various shapes, including plates, spheres and rods. The resultant NaYF4:Yb/Er@CS@Ag2S system possesses both upconversion luminescence (UCL) properties of NaYF4:Yb/Er and a good photothermal conversion effect of Ag2S, and is a promising candidate for UCL imaging guided PTT of cancer.

Plasmonic Pt Superstructures with Boosted Near-Infrared Absorption and Photothermal Conversion Efficiency in the Second Biowindow for Cancer Therapy.

Photothermal therapy triggered by near-infrared light in the second biowindow (NIR-II) has attracted extensive interest owing to its deeper penetration depth of biological tissue, lower photon scattering, and higher maximum permissible exposure. In spite of noble metals showing great potential as the photothermal agents due to the tunable localized surface plasmon resonance, the biological applications of platinum are rarely explored. Herein, a monocomponent hollow Pt nanoframe ("Pt Spirals"), whose superstructure is assembled with three levels (3D frame, 2D layered shells, and 1D nanowires), is reported. Pt Spirals exhibit outstanding photothermal conversion efficiency (52.5%) and molar extinction coefficients (228.7 m2 mol-1 ) in NIR-II, which are much higher than those of solid Pt cubes. Simulations indicate that the unique superstructure can be a significant cause for improving both adsorption and the photothermal effect simultaneously in NIR-II. The excellent photothermal effect is achieved and subsequently verified in in vitro and in vivo experiments, along with superb heat-resistance properties, excellent photostability, and a prominent effect on computed tomography (CT) imaging, demonstrating that Pt Spirals are promising as effective theranostic platforms for CT imaging-guided photothermal therapy.

Ultrafast synthesis of ultrasmall polyethylenimine-protected AgBiS2 nanodots by "rookie method" for in vivo dual-modal CT/PA imaging and simultaneous photothermal therapy.

Developing a biocompatible nanotheranostic platform integrating diagnostic and therapeutic functions is a great prospect for cancer treatment. However, it is still a great challenge to synthesize nanotheranostic agents using an ultra-facile method. In the research reported here, ultrasmall polyethylenimine-protected silver bismuth sulfide (PEI-AgBiS2) nanodots were successfully synthesized using an ultra-facile and environmentally friendly strategy (1 min only at room temperature), which could be described as a "rookie method". PEI-AgBiS2 nanodots show good monodispersity and biocompatibility. For the first time, PEI-AgBiS2 nanodots were reported as a powerful and safe nanotheranostic agent for cancer treatment. PEI-AgBiS2 nanodots exhibit excellent computed tomography (CT) and photoacoustic (PA) dual-modal imaging ability, which could effectively guide photothermal cancer therapy. Furthermore, PEI-AgBiS2 nanodots exhibit a high photothermal conversion efficiency (η = 35.2%). The photothermal therapy (PTT) results demonstrated a highly efficient tumor ablation ability. More importantly, the blood biochemistry and histology analyses verify that the PEI-AgBiS2 nanodots have negligible long-term toxicity. This work highlights that PEI-AgBiS2 nanodots produced using this extremely effective method are a high-performance and safe PTT agent. These findings open a new gateway for synthesizing nanotheranostic agents by using this ultra-facile method in the future.

Simple construction of Cu2-xS:Pt nanoparticles as nanotheranostic agent for imaging-guided chemo-photothermal synergistic therapy of cancer.

Synergistic therapy has attracted intense attention in medical treatment because it can make up for the disadvantages of single therapy and greatly improve the efficacy of cancer treatment. However, it remains a challenge to build a simple system to achieve synergistic therapy. In this study, X-ray computed tomography (CT) imaging-guided chemo-photothermal synergistic therapy can be easily achieved by simple construction of Cu2-xS:Pt(0.3)/PVP nanoparticles (NPs). Cu2-xS:Pt(0.3)/PVP NPs can passively accumulate within the tumor sites, thus ensuring that many Cu2-xS:Pt(0.3)/PVP NPs are brought into the tumor cells, which can be confirmed by the results of cellular uptake, imaging, and nanoparticle biodistribution. It can be verified that the platinum ions can be released from Cu2-xS:Pt(0.3)/PVP NPs under 808 nm laser irradiation. Simultaneously, Pt(iv) ions are reduced to Pt(ii) ions by excess glutathione and then, they exhibit chemo-anticancer activities. In addition, Cu2-xS:Pt(0.3)/PVP NPs can be used as an effective photothermal agent. The results demonstrate that the efficient tumor growth inhibition effect can be realized from the mice treated with Cu2-xS:Pt(0.3)/PVP NPs under 808 nm laser irradiation by chemo-photothermal synergistic therapy. Furthermore, Cu2-xS:Pt(0.3)/PVP NPs can be thoroughly cleared through feces in a short time, showing high biosafety for further potential clinical translations.

Near-infrared optical and X-ray computed tomography dual-modal imaging probe based on novel lanthanide-doped K0.3Bi0.7F2.4 upconversion nanoparticles.

A novel K0.3Bi0.7F2.4 upconversion (UC) matrix has been prepared successfully by a solvothermal method. K0.3Bi0.7F2.4:Yb3+/Ln3+ (Ln = Er, Ho, Tm) upconversion nanoparticles (UCNPs) show a corresponding excellent upconversion luminescence (UCL) under 980 nm laser irradiation. Especially, the strong near-infrared (NIR) UCL of K0.3Bi0.7F2.4:20% Yb3+/0.5% Tm3+ (abbreviated as BYT) UCNPs is suitable for deep tissue optical imaging. Moreover, the high X-ray absorption coefficient of Bi makes the as-prepared UCNPs favorable for computed tomography (CT) imaging. The citrate-coated BYT UCNPs show good biocompatibility through the MTT assay towards HeLa cells and low hemolytic properties by hemolysis assay, which could be applied for in vivo optical and CT imaging. After intravenous injection of citrate-coated BYT UCNPs for one month, blood biochemistry and histology analysis of mice suggest the UCNPs have a negligible toxicity in vivo, implying citrate-coated BYT could be employed as a safe bioprobe for NIR optical and CT dual-modal imaging.

Multifunctional Cu-Ag2S nanoparticles with high photothermal conversion efficiency for photoacoustic imaging-guided photothermal therapy in vivo.

Photothermal therapy (PTT) has attracted increasing interest and become widely used in cancer therapy owing to its noninvasiveness and low level of systemic adverse effects. However, there is an urgent need to develop biocompatible and multifunctional PTT agents with high photothermal conversion efficiency. Herein, biocompatible Cu-Ag2S/PVP nanoparticles (NPs) with strong near-infrared absorption and high photothermal conversion efficiency were successfully synthesized for high-performance photoacoustic (PA) imaging-guided PTT in vivo. The novel Cu-Ag2S/PVP NPs feature high photothermal conversion efficiency (58.2%) under 808 nm light irradiation, noticeably higher than those of most reported PTT agents. Because of their good dispersibility, Cu-Ag2S/PVP NPs passively accumulate within tumors via the enhanced permeability and retention effect, which can be confirmed by PA imaging, photothermal performance, and biodistribution in vivo. Furthermore, Cu-Ag2S/PVP NPs are thoroughly cleared through feces and urine within seven days, indicating a high level of biosafety for further potential clinical translation.

PEGylated GdF3:Fe Nanoparticles as Multimodal T1/T2-Weighted MRI and X-ray CT Imaging Contrast Agents.

Contrast agents for multimodal imaging are in high demand for cancer diagnosis. To date, integration of T1/T2-weighted magnetic resonance imaging (MRI) and X-ray computed tomography (CT) imaging capabilities in one system to obtain an accurate diagnosis still remains challenging. In this work, biocompatible PEGylated GdF3:Fe nanoparticles (PEG-GdF3:Fe NPs) were reasonable designed and synthesized as multifunctional contrast agents for efficient T1/T2-weighted MRI and X-ray CT multimodal imaging. Owing to the enhanced permeability and retention effect in vivo, strong T1 contrast, evident T2 contrast, and X-ray CT signals in a tumor lesion can be observed after intravenous injection of PEG-GdF3:Fe NPs. Therefore, PEG-GdF3:Fe NPs could be used as potential multimodal contrast agents for cancer diagnosis.

Ultrafast Synthesis of Novel Hexagonal Phase NaBiF4 Upconversion Nanoparticles at Room Temperature.

Upconversion (UC) nanoparticles (UCNPs) have evoked considerable attention in many fields owing to their fascinating features. However, rigorous synthesis conditions and expensive raw materials often limit their further applications. Here, a novel hexagonal phase NaBiF4 UC matrix through a very facile method (one min only at room temperature) is synthesized. The nanoparticles show good monodispersity with uniform size. Under the 980 nm irradiation, Yb3+ /Ln3+ (Ln = Er, Ho, Tm) codoped NaBiF4 nanoparticles show excellent UC luminescence (UCL). This super facile synthesis strategy and excellent matrix materials enable to achieve UCL in such low temperature, opening a new gateway for the UCNPs applied to a variety of areas in the future.

Optimization of Bi3+ in Upconversion Nanoparticles Induced Simultaneous Enhancement of Near-Infrared Optical and X-ray Computed Tomography Imaging Capability.

Bioimaging probes have been extensive studied for many years, while it is still a challenge to further improve the image quality for precise diagnosis in clinical medicine. Here, monodisperse NaGdF4:Yb3+,Tm3+,x% Bi3+ (abbreviated as GYT-x% Bi3+, x = 0, 5, 10, 15, 20, 25, 30) upconversion nanoparticles (UCNPs) have been prepared through the solvothermal method. The near-infrared upconversion emission intensity of GYT-25% Bi3+ has been enhanced remarkably than that of NaGdF4:Yb3+,Tm3+ (GYT) with a factor of ∼60. Especially, the near-infrared upconversion emission band centered at 802 nm is 150 times stronger than the blue emission band of GYT-25% Bi3+ UCNPs. Such high ratio of NIR/blue UCL intensity could reduce the damage to tissues in the bioimaging process. The possibility of using GYT-25% Bi3+ UCNPs with strong near-infrared upconversion emission for optical imaging in vitro and in vivo was performed. Encouragingly, the UCL imaging penetration depth can be achieved as deep as 20 mm. Importantly, GYT-25% Bi3+ UCNPs exhibit a much higher X-ray computed tomography (CT) contrast efficiency than GYT and iodine-based contrast agent under the same clinical conditions, due to the high X-ray attenuation coefficient of bismuth. Hence, simultaneous remarkable enhancement of NIR emission and X-ray CT signal in upconversion nanoparticles could be achieved by optimizing the doping concentration of Bi3+ ions. Additionally, Gd3+ ions in the UCNPs endow GYT-25% Bi3+ UCNPs with T1-weighted magnetic resonance (MR) imaging capability.

Core-shell-shell heterostructures of α-NaLuF4:Yb/Er@NaLuF4:Yb@MF2 (M = Ca, Sr, Ba) with remarkably enhanced upconversion luminescence.

Core-shell-shell heterostructures of α-NaLuF4:Yb/Er@NaLuF4:Yb@MF2 (M = Ca, Sr, Ba) have been successfully fabricated via the thermal decomposition method. Upconversion nanoparticles (UCNPs) were characterized by powder X-ray diffraction (XRD), transmission electron microscopy (TEM), upconversion luminescence (UCL) spectroscopy, etc. Under 980 nm excitation, the emission intensities of the UCNPs are remarkably enhanced after coating the MF2 (M = Ca, Sr, and Ba) shell. Among these samples, CaF2 coated UCNPs show the strongest overall emission, while BaF2 coated UCNPs exhibit the longest lifetime. These results demonstrate that alkaline earth metal fluorides are ideal materials to improve the UCL properties. Meanwhile, although the lattice mismatch between the ternary NaREF4 core and the binary MF2 (M = Sr and Ba) shell is relatively large, the successfully synthesized NaLuF4:Yb/Er@NaLuF4:Yb@MF2 indicates a new outlook on the fabrication of heterostructural core-shell UCNPs.

Rational design of Nd(3+)-sensitized multifunctional nanoparticles with highly dominant red emission.

Controlling excitation and emission wavelengths on demand is very significant in bioimaging. Up-conversion nanoparticles (UCNPs) emit visible light upon near-infrared (NIR) light excitation and are well studied in bioimaging. Red emission is usually preferred to green due to its higher tissue penetration depth in bioimaging. Herein, dominant red emission has been achieved under 808 nm excitation based on the designed α-NaYbF4:Mn(2+)/Er(3+)@NaLuF4:Mn(2+)/Yb(3+)@NaNdF4:Yb(3+)@NaGdF4 (C@S1@S2@S3) nanostructure. The rationally designed interlayer shell NaLuF4:Mn(2+)/Yb(3+) could efficiently filter unwanted energy back-transfer from Er(3+) to Nd(3+) and the outmost shell NaGdF4 could prevent excitation energy from surface-related quenching. The lifetime of (4)F9/2→(4)I15/2 transition of Er(3+) could be as high as 0.7 ms. Moreover, C@S1@S2@S3 UCNPs also possess effective contrast efficiency for both X-ray computed tomography (CT) and magnetic resonance (MR) imaging. The designed multifunctional UCNPs could be used as a potential multimodal bioprobe in bioimaging applications.