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Nanoparticles engineered to combat cancer and other life-threatening diseases may significantly improve patient outcomes. However, inefficient nanoparticle delivery to tumors limits their use and necessitates the development of complex delivery approaches. Here, we examine this issue by harnessing the tumor-homing abilities of human mesenchymal stem cells (MSCs) to deliver a decoupled theranostic complex of rare earth-doped nanoparticles (dNPs) and photosensitizer chlorin e6 (Ce6) to tumors. We show that both bone-marrow- and skin-derived MSCs can transport the dNP-Ce6 complex inside tumor spheroids, which is challenging to accomplish by passive delivery alone. MSCs deliver the dNP-Ce6 complex across the tumor spheroid, facilitating more effective photodynamic damage and tumor destruction than passively accumulated dNP-Ce6. The dNP-Ce6 complex also provides the built-in ability to monitor the MSC migration without causing undesired phototoxicity, which is essential for maximal and side-effect-free delivery of nanoparticles. Our results demonstrate how MSCs can be used as delivery vehicles for the transportation of the dNP-Ce6 complex, addressing the limitations of passive nanoparticle delivery and providing light-based theranostics.

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Development of efficient portable sensors for accurately detecting biomarkers is crucial for early disease diagnosis, yet remains a significant challenge. To address this need, we introduce the enhanced luminescence lateral-flow assay, which leverages highly luminescent upconverting nanoparticles (UCNPs) alongside a portable reader and a smartphone app. The sensor's efficiency and versatility were shown for kidney health monitoring as a proof of concept. We engineered Er3+- and Tm3+-doped UCNPs coated with multiple layers, including an undoped inert matrix shell, a mesoporous silica shell, and an outer layer of gold (UCNP@mSiO2@Au). These coatings synergistically enhance emission by over 40-fold and facilitate biomolecule conjugation, rendering UCNP@mSiO2@Au easy to use and suitable for a broad range of bioapplications. Employing these optimized nanoparticles in lateral-flow assays, we successfully detected two acute kidney injury-related biomarkers─kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)─in urine samples. Using our sensor platform, KIM-1 and NGAL can be accurately detected and quantified within the range of 0.1 to 20 ng/mL, boasting impressively low limits of detection at 0.28 and 0.23 ng/mL, respectively. Validating our approach, we analyzed clinical urine samples, achieving biomarker concentrations that closely correlated with results obtained via ELISA. Importantly, our system enables biomarker quantification in less than 15 min, underscoring the performance of our novel UCNP-based approach and its potential as reliable, rapid, and user-friendly diagnostics.

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Today, diabetes mellitus is one of the most common diseases that affects the population on a worldwide scale. Patients suffering from this disease are required to control their blood-glucose levels several times a day through invasive methods such as piercing their fingers. Our NaGdF4: 5% Er3+, 3% Nd3+ nanoparticles demonstrate a remarkable ability to detect D-glucose levels by analysing alterations in their red-to-green ratio, since this sensitivity arises from the interaction between the nanoparticles and the OH groups present in the D-glucose molecules, resulting in discernible changes in the emission of the green and red bands. These luminescent sensors were implemented and tested on paper substrates, offering a portable, low-cost and enzyme-free solution for D-glucose detection in aqueous solutions with a limit of detection of 22 mg/dL. With this, our study contributes to the development of non-invasive D-glucose sensors, holding promising implications for managing diabetes and improving overall patient well-being with possible future applications in D-glucose sensing through tear fluid.

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Lanthanide-doped up-converting nanoparticles (UCNPs) have emerged as promising biomedical tools in recent years. Most research efforts were devoted to the synthesis of inorganic cores with the optimal physicochemical properties. However, the careful design of UCNPs with the adequate surface coating to optimize their biological performance still remains a significant challenge. Here, we propose the functionalization of UCNPs with four distinct types of surface coatings, which were compared in terms of the provided colloidal stability and resistance to degradation in different biological-relevant media, including commonly avoided analysis in acidic lysosomal-mimicking fluids. Moreover, the influence of the type of particle surface coating on cell cytotoxicity and endocytosis/exocytosis was also evaluated. The obtained results demonstrated that the functionalization of UCNPs with poly(isobutylene-alt-maleic anhydride) grafted with dodecylamine (PMA-g-dodecyl) constitutes an outstanding strategy for their subsequent biomedical application, whereas poly(ethylene glycol) (PEG) coating, although suitable for colloidal stability purposes, hinders extensive cell internalization. Conversely, surface coating with small ligand were found not to be suitable, leading to large degradation degrees of UCNPs. The analysis of particle' behavior in different biological media and in vitro conditions here performed pretends to help researchers to improve the design and implementation of UCNPs as theranostic nanotools.

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In this study, spherical or hexagonal NaYF4:Yb,Er nanoparticles (UCNPs) with sizes of 25 nm (S-UCNPs) and 120 nm (L-UCNPs) were synthesized by high-temperature coprecipitation and subsequently modified with three kinds of polymers. These included poly(ethylene glycol) (PEG) and poly(N,N-dimethylacrylamide-co-2-aminoethylacrylamide) [P(DMA-AEA)] terminated with an alendronate anchoring group, and poly(methyl vinyl ether-co-maleic acid) (PMVEMA). The internalization of nanoparticles by rat mesenchymal stem cells (rMSCs) and C6 cancer cells (rat glial tumor cell line) was visualized by electron microscopy and the cytotoxicity of the UCNPs and their leaches was measured by the real-time proliferation assay. The comet assay was used to determine the oxidative damage of the UCNPs. An in vivo study on mice determined the elimination route and potential accumulation of UCNPs in the body. The results showed that the L- and S-UCNPs were internalized into cells in the lumen of endosomes. The proliferation assay revealed that the L-UCNPs were less toxic than S-UCNPs. The viability of rMSCs incubated with particles decreased in the order S-UCNP@Ale-(PDMA-AEA) > S-UCNP@Ale-PEG > S-UCNPs > S-UCNP@PMVEMA. Similar results were obtained in C6 cells. The oxidative damage measured by the comet assay showed that neat L-UCNPs caused more oxidative damage to rMSCs than all coated UCNPs while no difference was observed in C6 cells. An in vivo study indicated that L-UCNPs were eliminated from the body via the hepatobiliary route; L-UCNP@Ale-PEG particles were almost eliminated from the liver 96 h after intravenous application. Pilot fluorescence imaging confirmed the limited in vivo detection capabilities of the nanoparticles.

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A laboratory-based lateral flow (LF) test that utilizes up-converting reporter particles (UCP) for ultrasensitive quantification of Schistosoma circulating anodic antigen (CAA) in urine is a well-accepted test to identify active infection. However, this UCP-LF CAA test requires sample pre-treatment steps not compatible with field applications. Flow, a new low-cost disposable, allows integration of large-volume pre-concentration of urine analytes and LF detection into a single field-deployable device. We assessed a prototype Flow-Schistosoma (Flow-S) device with an integrated UCP-LF CAA test strip, omitting all laboratory-based steps, to enable diagnosis of active Schistosoma infection in the field using urine. Flow-S is designed for large-volume (5-20 mL) urine, applying passive paper-based filtration and antibody-based CAA concentration. Samples tested for schistosome infection were collected from women of reproductive age living in a Tanzania region where S. haematobium infection is endemic. Fifteen negative and fifteen positive urine samples, selected based on CAA levels quantified in paired serum, were analyzed with the prototype Flow-S. The current Flow-S prototype, with an analytical lower detection limit of 1 pg CAA/mL, produced results correlated with the laboratory-based UCP-LF CAA test. Urine precipitates occurred in frozen banked samples and affected accurate quantification; however, this should not occur in fresh urine. Based on the findings of this study, Flow-S appears suitable to replace the urine pre-treatment required for the laboratory-based UCP-LF CAA test, thus allowing true field-based applications with fresh urine samples. The urine precipitates observed with frozen samples, though less important given the goal of testing fresh urines, warrant additional investigation to evaluate methods for mitigation. Flow-S devices permit testing of pooled urine samples with applications for population stratified testing. A field test with fresh urine samples, a further optimized Flow-S device, and larger statistical power has been scheduled.

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Drug-induced liver injury (DILI) is a frequent adverse drug reaction. The current clinical diagnostic methods are inadequate for accurate and early detection of DILI due to the lack of effective diagnostic biomarkers. Hepatocyte-specific miR-122 is released from injured hepatocytes promptly and its efflux is significantly correlated with the progression of DILI. Therefore, achieving precise in situ detection of miR-122 with high sensitivity is vital for early visualization of DILI. Herein, a new nanoprobe, consisting of miR-122 aptamer, upconversion nanoparticles (UCNPs) and Prussian blue nanoparticles (PBNPs) was introduced for the early and sensitive detection of DILI in situ. As the nanoprobes reached in the liver, miR-122 aptamer-based entropy-driven strand displacement (ESDR) signal amplification reaction was triggered and luminescence resonance energy transfer (LRET) between UCNPs and PBNPs was responded to achieve the high-fidelity detection of DILI. A negative correlation was observed between the intensity of upconversion luminescence (UCL) and the concentration of miR-122. UCL imaging conducted both in vivo and ex vivo indicated that a reduction in miR-122 concentration led to an increase in UCL intensity, revealing a precise state of DILI. The detection technique demonstrated a positive correlation between signal intensity and severity, offering a more straightforward and intuitive method of visualizing DILI.

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External stimuli can trigger changes in temperature, concentration, and momentum between micromotors and the medium, causing their propulsion and enabling them to perform different tasks with improved kinetic efficiencies. Light-activated micromotors are attractive systems that achieve improved motion and have the potential for high spatiotemporal control. Photophoretic swarming motion represents an attractive means to induce micromotor movement through the generation of temperature gradients in the medium, enabling the micromotors to move from cold to hot regions. The micromotors studied herein are assembled with Fe3O4 nanoparticles, and NaGdF4:Yb3+,Er3+/NaGdF4:Yb3+ and LiYF4:Yb3+,Tm3+ upconverting nanoparticles. The Fe3O4 nanoparticles were localized to one hemisphere to produce a Janus architecture that facilitates improved upconversion luminescence with the upconverting nanoparticles distributed throughout. Under 976 nm excitation, Fe3O4 nanoparticles generate the temperature gradient, while the upconverting nanoparticles produce visible light that is used for micromotor motion tracking and triggering of reactive oxygen species generation. As such, the motion and application of the micromotors are achieved using a single excitation wavelength. To demonstrate the practicality of this system, curcumin was adsorbed to the micromotor surface and degradation of Rhodamine B was achieved with kinetic rates that were over twice as fast as the static micromotors. The upconversion luminescence was also used to track the motion of the micromotors from a single image frame, providing a convenient means to understand the trajectory of these systems. Together, this system provides a versatile approach to achieving light-driven motion while taking advantage of the potential applications of upconversion luminescence such as tracking and detection, sensing, nanothermometry, particle velocimetry, photodynamic therapy, and pollutant degradation.

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If the appropriate immobilization method and carrier support are not selected, partial decreases in the activity of enzymes may occur after immobilization. Herein, to overcome this challenge, an excitation mechanism that enables energy transfer was proposed. Modified upconverting nanoparticles (UCNPs) were constructed and the important role of near-infrared (NIR) excitation in enhancing the catalytic activity of the enzyme was demonstrated. For this purpose, UCNPs were first synthesized via the hydrothermal method, functionalized with isocyanate groups, and then, PEG-L-ASNase was immobilized via covalent binding. UCNPs with and without PEG-L-ASNase were extensively characterized by different methods. These supports had immobilization yield and activity efficiency of >96 % and 78 %, respectively. Moreover, immobilized enzymes exhibited improved pH, thermal, and storage stability. In addition, they retained >65 % of their initial activity even after 20 catalytic cycles. Biochemical and histological findings did not indicate a trend of toxicity in rats due to UCNPs. Most importantly, PEG-L-ASNase activity was triggered approximately 5- and 2-fold under in vitro and in vivo conditions, respectively. Overall, it is anticipated that this pioneering work will shed new light on the realistic and promising usage of NIR-excited UCNPs for the immobilization of enzymes in expensive and extensive applications.

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The photon upconverting properties of lanthanide-doped nanoparticles drive their applications in imaging, optoelectronics, and additive manufacturing. To maximize their brightness, these upconverting nanoparticles (UCNPs) are often synthesized as core/shell heterostructures. However, the large numbers of compositional and structural parameters in multishell heterostructures make optimizing optical properties challenging. Here, we demonstrate the use of Bayesian optimization (BO) to learn the structure and design rules for multishell UCNPs with bright ultraviolet and violet emission. We leverage an automated workflow that iteratively recommends candidate UCNP structures and then simulates their emission spectra using kinetic Monte Carlo. Yb3+/Er3+- and Yb3+/Er3+/Tm3+-codoped UCNP nanostructures optimized with this BO workflow achieve 10- and 110-fold brighter emission within 22 and 40 iterations, respectively. This workflow can be expanded to structures with higher compositional and structural complexity, accelerating the discovery of novel UCNPs while domain-specific knowledge is being developed.

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Bovine tuberculosis (bTB), caused by Mycobacterium bovis (M. bovis) infection in cattle, is an economically devastating chronic disease for livestock worldwide. Efficient disease control measures rely on early and accurate diagnosis using the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs), followed by culling of positive animals. Compromised performance of TST and IGRA, due to BCG vaccination or co-infections with non-tuberculous mycobacteria (NTM), urges improved diagnostics. Lateral flow assays (LFAs) utilizing luminescent upconverting reporter particles (UCP) for quantitative measurement of host biomarkers present an accurate but less equipment- and labor-demanding diagnostic test platform. UCP-LFAs have proven applications for human infectious diseases. Here, we report the development of UCP-LFAs for the detection of six bovine proteins (IFN-γ, IL-2, IL-6, CCL4, CXCL9, and CXCL10), which have been described by ELISA as potential biomarkers to discriminate M. bovis infected from naïve and BCG-vaccinated cattle. We show that, in line with the ELISA data, the combined PPDb-induced levels of IFN-γ, IL-2, IL-6, CCL4, and CXCL9 determined by UCP-LFAs can discriminate M. bovis challenged animals from naïve (AUC range: 0.87-1.00) and BCG-vaccinated animals (AUC range: 0.97-1.00) in this cohort. These initial findings can be used to develop a robust and user-friendly multi-biomarker test (MBT) for bTB diagnosis.

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Photoaffinity labeling (PAL) has blossomed into a powerful and versatile tool for capture and identification of biomolecular targets. However, low labeling efficiency for specific targets such as lectins, the tedious process for protein purification, inevitable cellular photodamage, and less tissue penetration of UV light are significant challenges. Herein, we reported a near-infrared (NIR) light-driven photoaffinity labeling approach using upconverting nanoparticle (UCNP)-based photoactive probes, which were constructed by assembling photoactive groups and ligands onto NaYF4:Yb,Tm nanoparticles. The novel probes were easily prepared and functionalized, and the labeled proteins can be isolated and purified through simple centrifugation and washing. The advantages of this approach were demonstrated by labeling and isolation of peanut agglutinin (PNA), asialoglycoprotein receptor (ASGPR), and human carbonic anhydrase II (hCAII) from mixed proteins or cell lysates with good selectivity and efficiency, especially for PNA and ASGPR, two lectins that showed low binding affinity to their ligands. More importantly, successful labeling of PNA through pork tissues and ASGPR in mice strongly proved the good tissue penetrating capacity of NIR light and the application potential of UCNP-based photoactive probes for protein labeling in vivo. Biosafety of this approach was experimentally validated by enzyme, cell, and animal work, and we demonstrated that NIR light caused minimal photodamage to enzyme activity compared to UV light, and the UCNP-based photoactive probe presents good biosafety both in vitro and in vivo. We believe that this novel PAL approach will provide a promising tool for study of ligand-protein interactions and identification of biomolecular targets.

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The properties of upconverting nanoparticles (UCNPs) are crucial for their applications in biomedicine. For studies of organisms and biological materials, the penetration depth of excitation light is also essential as the depth from which the luminescence can be detected. Currently, many researchers are trying to obtain UCNPs with intense emission under excitation wavelengths from the biological transparency windows to increase the penetration depth. However, studies comparing the properties of various types of UCNPs in real conditions are rare. This article shows how deep the 808, 975, 1208, and 1532 nm laser radiation penetrates human blood. Moreover, we determined how thick a layer of blood still permits for observation of the luminescence signal. The measured luminescence properties indicated that the near-infrared light could pass through the blood even to a depth of 7.5 mm. The determined properties of core/shell NaErF4/NaYF4 materials are the most advantageous, and their emission is detectable through 3.0 mm of blood layer using a 1532 nm laser. We prove that the NaErF4/NaYF4 UCNPs can be perfect alternatives for the most studied NaYF4:Yb3+,Er3+/NaYF4. Additionally, the setup proposed in this article can potentially decrease reliance on animal testing in initial biomedicine research.

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In this study, we report hybrid crystalline lanthanide-containing 3D covalent organic framework (Ln@3D COF) materials that are suitable for temperature sensing applications. Different routes to obtain these hybrid materials were tested and compared for material quality and thermometric properties. In the first approach, a bipyridine-containing 3D COF (Bipy COF) was grafted with a range of visible emitting lanthanide (Eu3+, Tb3+, Dy3+, and Eu3+/Tb3+) ß-diketonate complexes. In the second approach, a novel nanocomposite material was prepared by embedding NaYF4:Er,Yb nanoparticles on the surface of a nonfunctionalized 3D COF (COF-300). To the best of our knowledge, the luminescent materials developed here are the first 3D COFs to be tested as ratiometric temperature sensors. In fact, for the Bipy COF, two different types of thermometers were tested (the Eu3+/Tb3+ system and a rare Dy3+ system), with both showing excellent temperature sensing properties. The reported NaYF4:Er,Yb/COF-300 nanocomposite material combines upconverting nanoparticles with 3D COFs, similar to previously reported metal organic framework (MOF) nanocomposite materials; however, this type of hybrid material has not yet been explored for COFs. As such, our findings open a new pathway toward potential multifunctional materials that can combine thermometry with other modalities, such as catalysis or drug delivery, in just one nanocomposite material.

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Photon upconversion is an intensively investigated phenomenon in the materials sciences due to its unique applications, mainly in biomedicine for disease prevention and treatment. This study reports the synthesis and properties of tetragonal LiYbF4:Tm3+@LiYF4 core@shell nanoparticles (NPs) and their applications. The NPs had sizes ranging from 18.5 to 23.7 nm. As a result of the energy transfer between Yb3+ and Tm3+ ions, the synthesized NPs show intense emission in the ultraviolet (UV) range up to 347 nm under 975 nm excitation. The bright emission in the UV range allows for singlet oxygen generation in the presence of hematoporphyrin on the surface of NPs. Our studies show that irradiation with a 975 nm laser of the functionalized NPs allows for the production of amounts of singlet oxygen easily detectable by Singlet Oxygen Sensor Green. The high emission intensity of NPs at 800 nm allowed the application of the synthesized NPs in an upconversion-linked immunosorbent assay (ULISA) for highly sensitive detection of the nucleoprotein from SARS-CoV-2, the causative agent of Covid-19. This article proves that LiYbF4:Tm3+@LiYF4 core@shell nanoparticles can be perfect alternatives for the most commonly studied upconverting NPs based on the NaYF4 host compound and are good candidates for biomedical applications.

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Materials capable of emitting ultraviolet (UV) radiation are sought for applications ranging from theranostics or photodynamic therapy to specific photocatalysis. The nanometer size of these materials, as well as excitation with near-infrared (NIR) light, is essential for many applications. Tetragonal tetrafluoride LiY(Gd)F4nanocrystalline host for up-converting Tm3+-Yb3+activator-sensitizer pair is a promising candidate to achieve UV-vis up-converted radiation under NIR excitation, important for numerous photo-chemical and bio-medical applications. Here, we provide insights into the structure, morphology, size and optical properties of up-converting LiYF4:25%Yb3+0.5%Tm3+colloidal nanocrystals, where 1, 5, 10, 20, 30 and 40% of Y3+ions were substituted with Gd3+ions. Low gadolinium dopant concentrations modify the size and up-conversion luminescence, while the Gd3+doping that is exceeding the structure resistance limit of the tetragonal LiYF4results in appearance of foreign phase and significant decrease of luminescence intensity. The intensity and kinetic behavior of Gd3+up-converted UV emission are also analyzed for various gadolinium ions concentrations. The obtained results form a background for further optimized materials and applications based on LiYF4nanocrystals.

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Background: Modern medicine requires intensive research to find new diagnostic and therapeutic solutions. Recently, upconverting nanoparticles (UCNPs) doped with lanthanide ions have attracted significant attention. Methods: The efficient internalization of UCNPs by cells was confirmed, and their precise cellular localization was determined by electron microscopy and confocal studies. Results: UCNPs colocalized only with specific organelles, such as early endosomes, late endosomes and lysosomes. Furthermore, experiments with chemical inhibitors confirmed the involvement of endocytosis in UCNPs internalization and helped select several mechanisms involved in internalization. Exposure to selected UCNPs concentrations did not show significant cytotoxicity, induction of oxidative stress or ultrastructural changes in cells. Conclusion: This study suggests that UCNPs offer new diagnostic options for biomedical infrared imaging.

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Upconverting nanoparticles (UCNPs) compose a class of luminescent materials that utilize the unique wavelength-converting properties of lanthanide (Ln) ions for light-harvesting applications, photonics technologies, and biological imaging and sensing experiments. Recent advances in UCNP design have shed light on the properties of local color centers, both intrinsic and controllably induced, within these materials and their potential influence on UCNP photophysics. In this review, we describe fundamental studies of color centers in Ln-based materials, including research into their origins and their roles in observed photodarkening and photobrightening mechanisms. We place particular focus on the new functionalities that are enabled by harnessing the properties of color centers within Ln-doped nanocrystals, illustrated through applications in afterglow-based bioimaging, X-ray detection, all-inorganic nanocrystal photoswitching, and fully rewritable optical patterning and memory.

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Significance: Phantoms play a critical role in the development of biophotonics techniques. There is a lack of novel phantom tools in the emerging field of upconverting nanoparticles (UCNPs) for biophotonics application. This work provides a range of UCNP-based phantom tools and a manufacturing recipe to bridge the gap and accelerate the development of UCNP-based biophotonics applications. Aim: The study aims to provide a well-characterized UCNP-based solid phantom recipe and set of phantom tools to address a wide range of UCNP-based biophotonics applications. Approach: A solid phantom recipe based on silicone matrix was developed to manufacture UCNP-based phantoms. A lab built UCNP imaging system was used to characterize upconverted fluorescence emission of phantoms for linearity, homogeneity, and long-term stability. A photon time-of-flight spectroscopy technique was used to characterize the optical properties of the phantoms. Results: In total, 24 phantoms classified into 4 types, namely homogeneous, multilayer, inclusion, and base phantoms, were manufactured. The phantoms exhibit linear behavior over the dosage range of UCNPs. The phantoms were found to be stable over a limited observed period of 4 months with a coefficient of variation of < 4 % . The deep tissue imaging case showed that increasing the thickness of tissue reduced the UCNP emission. Conclusions: A first-of-its-kind UCNP-based solid phantom recipe was developed, and four types of UCNP phantom tools to explore biophotonics applications were presented. The UCNP phantoms exhibited a linear behavior with dosage and were stable over time. An example case showed the potential use of the phantom for deep tissue imaging applications. With recent advance in the use of UCNPs for biophotonics, we believe our recipe and tools will play a pivotal role in the growth of the UCNPs for biophotonics applications.

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Photodynamic therapy (PDT) is a promising strategy for cancer treatment. However, a poor tissue penetration of activation light and low target specificity seriously hindered the clinical application of PDT. Here, we designed and constructed a size-controllable nanosystem (UPH) with inside-out responsive for deep PDT with enhanced biosafety. To obtain nanoparticles with the best quantum yield, a series of core-shell nanoparticles (UCNP@nPCN) with different thicknesses were synthesized by a layer-by-layer self-assembly method to incorporate a porphyritic porous coordination network (PCN) onto the surface of upconverting nanoparticles (UCNPs), followed by coating with hyaluronic acid (HA) on the surface of nanoparticles with optimized thickness to form the UPH nanoparticles. With the aid of HA, the UPH nanoparticles were capable of preferentially enriching in tumor sites and specific endocytosis by CD44 receptors as well as responsive degradation by hyaluronidase in cancer cells after intravenous administration. Subsequently, after being activated by strong penetrating 980 nm near-infrared light (NIR), the UPH nanoparticles efficiently converted oxygen into strongly oxidizing reactive oxygen species based on the fluorescence resonance energy transfer (FRET) effect, thereby significantly inhibiting tumor growth. Experimental results in vitro and in vivo indicated that such dual-responsive nanoparticles successfully realize the photodynamic therapy of deep-seated cancer with negligible side effects, which showed great potential for potential clinical translational research.