Deep Penetration Research Articles

A collagenase-decorated Cu-based nanotheranostics: remodeling extracellular matrix for optimizing cuproptosis and MRI in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), characterized by a dense extracellular matrix (ECM), presents significant therapeutic challenges due to its poor prognosis and high resistance to chemotherapy. Current chemodrugs and diagnostic agents largely fail to cross the barrier posed by the ECM, which severely limits the PDAC theranostics. This study introduces a novel theranostic strategy using thioether-hybridized hollow mesoporous organosilica nanoparticles (dsMNs) for the co-delivery of copper (Cu) and disulfiram (DSF), aiming to induce cuproptosis in PDAC cells. Our approach leverages the ECM-degrading enzyme collagenase, integrated with dsMNs, to enhance drug penetration by reducing matrix stiffness. Furthermore, the innovative use of a pancreatic cancer cell membrane coating on the nanoparticles enhances tumor targeting and stability (dsMCu-D@M-Co). The multifunctional platform not only facilitates deep drug penetration and triggers cuproptosis effectively but also utilizes the inherent properties of Cu to serve as a T1-weighted magnetic resonance imaging (MRI) contrast agent. In vitro and in vivo assessments demonstrate significant tumor size reduction in PDAC-bearing mice, highlighting the dual functionality of our platform in improving therapeutic efficacy and diagnostic precision. This integrated strategy represents a significant advancement in the management of PDAC, offering a promising new direction for overcoming one of the most lethal cancers.Graphical

Research on the Advantages and Challenges of Replacing LEDs with Lasers in Functional Near-Infrared Spectroscopy Systems Based on Advanced Signal Processing Algorithms

Abstract: Functional near infrared spectroscopy (fNIRS) has received increasing attention as a non-invasive, portable brain hemodynamic monitoring tool due to its potential for use in natural Settings. Traditional fNIRS systems commonly use light-emitting diodes (LEDs) as light sources, which have become the mainstream choice because of their low cost, easy integration, low heat output, and availability of a variety of near-infrared wavelengths. However, LEDs are limited by their low optical output power and broad wavelength range, which restrict their effectiveness in deep tissue penetration and signal quality. In contrast, Laser Diodes (LD) have the advantages of good monochromaticity and high optical output power, which can provide deeper tissue penetration and higher signal stability. Therefore, this study explores the feasibility of using lasers instead of leds in fNIRS systems and their impact on signal quality and imaging depth. By comparing the performance of LED and laser-based fNIRS systems, it is evident that lasers provide significant improvements in signal quality and imaging depth, although they face challenges in terms of cost, thermal management, and safety. The research in this paper provides an important reference for the future design of fNIRS system, especially in the application scenarios requiring high precision imaging.

IMPACT OF LIGAND CONJUGATION OF PHYSICOCHEMICAL ATTRIBUTES OF POLYMERIC NANOPARTICLES OF ATYPICAL ANTIPSYCHOTIC DRUG FOR NOSE-TO-BRAIN DELIVERY

Objective: To formulate and characterize the ligand-conjugated chitosan nanoparticles of Ziprasidone Hydrochloride (ZH) and compare with its plain chitosan nanoparticles. Methods: Transferrin (Tf) conjugated Chitosan Nanoparticles (CH-NP) containing ZH were prepared by ionotropic gelation method by using modified chitosan and Tf. Physicochemical attributes of nanoparticles which can potentially impact the nose-to-brain delivery were evaluated. Results: The Tf-CH-NP has demonstrated 207.1 nm mean particle size, 87.6% entrapment efficiency with a release of 89.34% at 24 h and has shown about 2.22 times more release than drug suspension and about 4.5% more than plain CH-NP. The similar trend was observed in Ex vivo nasal permeation study. Its acceptability was shown in histomorphology study, where a minimal inflammation seen, that might be due to the pH of the formulation. There is deeper penetration with Tf-CH-NP, which is more promising for penetration into brain. Conclusion: The formulated Tf-CH-NP has a greater potential due to ligand conjugation to reach the brain and, facilitate targeted delivery and enables better treatment of schizophrenia at minimal doses.

Advances in Spectro-Microscopy Methods and their Applications in the Characterization of Perovskite Materials.

Perovskite materials are promising contenders as the active layer in light-harvesting and light-emitting applications if their long-term stability can be sufficiently increased. Chemical and structural engineering are shown to enhance long-term stability, but the increased complexity of the material system also leads to inhomogeneous functional properties across various length scales. Thus, scanning probe and high-resolution microscopy characterization techniques are needed to reveal the role of local defects and the results promise to act as the foundation for future device improvements. A look at the parameter space: technique-specific sample penetration depth versus probe size highlights a gap in current methods. High spatial resolution combined with a deep penetration depth is not yet achievable. However, multimodal measurement technique may be the key to covering this parameter space. In this perspective, current advanced spectro-microscopy methods which have been applied to perovskite materials are highlighted.

Cascade-catalysed nanocarrier degradation for regulating metabolism homeostasis and enhancing drug penetration on breast cancer

The abnormal structure of tumor vascular seriously hinders the delivery and deep penetration of drug in tumor therapy. Herein, an integrated and tumor microenvironment (TME)-responsive nanocarrier is designed, which can dilate vessle and improve the drug penetration by in situ releasing nitric oxide (NO). Briefly, S-nitroso-glutathione (GSNO) and curcumin (Cur) were encapsulatd into the Cu-doped zeolite imidazole framework-8 (Cu-ZIF-8) and modified with hyaluronic acid. The nanocarrier degradation in the weakly acidic of TME releases Cu2+, then deplete overexpressed intratumourally glutathione and transformed into Cu+, thus disrupting the balance between nicotinamide adenine dinucleotide phosphate and flavin adenine dinucleotide (NADPH/FAD) during the metabolism homeostasis of tumor. The Cu+ can generate highly toxic hydroxyl radical through the Fenton-like reaction, enhancing the chemodynamic therapeutic effect. In addition, Cu+ also decomposes GSNO to release NO by ionic reduction, leading to vasodilation and increased vascular permeability, significantly promoting the deep penetration of Cur in tumor. Afterwards, the orderly operation of cell cycle is disrupted and arrested in the S-phase to induce tumor cell apoptosis. Deep-hypothermia potentiated 2D/3D fluorescence imaging demonstrated nanocarrier regulated endogenous metabolism homeostasis of tumor. The cascade-catalysed multifunctional nanocarrier provides an approach to treat orthotopic tumor.

Why are the Category of "Unnecessary" Borrowings or Parallel Lexical Units Still Present in Standard Albanian Language?

Language, as a complete system of units and rules and at the same time a system not isolated, but open to changes, is the property of the society that uses it. Linguistic development and social development are accompanied by a mutual relationship between them, it would even be right to express the well-known definition that: there is no development that takes place in a society that does not leave its traces in the language system, especially in the system its lexicon. The developments that Albanian society has undergone in recent decades have made it possible for a relatively large number of borrowings to enter the Albanian language, mainly anglicisms. This phenomenon has caused a good part of Albanian linguists to be involved in the so-called cleaning process of relatively new borrowings or borrowings of the last decades in the Albanian language. Although discussions about the category of borrowed in the Albanian language constitute a very early linguistic reality, it should be noted that in the publications and scientific conferences of recent years it still continues to be treated as a matter of primary importance and as a growing phenomenon of continuous. Naturally, the perspectives of Albanian linguists on this field of study are different: some see the issue of borrowings as a very big damage done to the Albanian language, others see it as a natural state of language development, but not dangerous. for her. Despite the sometimes similar and approximate attitudes, but sometimes even contradictory, the aspect that unites most of the linguists who have dealt with this issue is related to the context in which the borrowed word is used, while the Albanian language has her answer. The questions we would raise in this context are: Should we call the phenomenon of the presence of "unnecessary borrowings" common in the Albanian language? The deep penetration into Albanian of these "parallel lexical units" or "synonyms" with the Albanian word should be seen and accepted as a natural development of the language and as a result of linguistic interaction in the conditions of global development, or should it be considered as a phenomenon that should be observed, even monitored, to some extent controlling its trends and developments?The aim of the paper is to create a description and reflection of the real situation of borrowings in Albanian, the place they have occupied in relation to the Albanian word and the approach of Albanian linguists and linguistics to this phenomenon. In another perspective, the paper aims to emphasize the irreplaceable role of the state and propose the creation of the missing law for the Albanian language in the Albanian legislation, with the aim of preserving the language from unnecessary linguistic elements that overlap the linguistic elements of its substratum autochthonous. Received: 16 June 2024 / Accepted: 5 October 2024 / Published: 05 November 2024

Spatiotemporally cascade-driven “Lipomicelles” enhance extracellular matrix penetration and remodel intercellular crosstalk in pulmonary fibrosis

Pulmonary fibrosis (PF) is an inevitable phase of many respiratory diseases with high mortality and limited effective treatments in the clinic. In PF, aberrant extracellular matrix (ECM) deposition is a significant pathological structural alteration that blocks intercellular crosstalk and hinders the deep penetration of therapeutics into lung tissues, reducing the effectiveness of conventional treatment strategies. Herein, a penetrating enhancer (Lipomicelles) composed of thermosensitive liposome shells loaded with collagenase IV and micellar cores containing thioketal bonds encapsulated with curcumin and decorated with cyclic RGDfc, is developed to alleviate PF. Specifically, Lipomicelles exhibit a cascade-responsive pattern to achieve precision delivery of curcumin through thermosensitivity, enhanced ECM penetration, site-specific targeting, and rapid release in injured alveolar epithelial type II cells (CellAEC2s). Subsequently, intercellular crosstalk is remodeled through the curcumin-mediated repair of CellAEC2s, combined with collagenase IV-mediated ECM degradation to inhibit myofibroblasts, ultimately achieving PF reversal. This work provides an innovative approach to enhance ECM penetration of therapeutics before remodeling intercellular crosstalk, addressing multi-phase PF therapy.

СТРАТЕГІЧНІ АЛЬТЕРНАТИВИ ВІДНОВЛЕННЯ КОНКУРЕНТОСПРОМОЖНОСТІ СФЕРИ ГОСТИННОСТІ УКРАЇНИ

Introduction. The field of hospitality is the basis for the development of the economies of many countries of the world. Ukraine is no exception. Although the full-scale invasion of the territory of Ukraine left its mark on this sector of the economy, causing great damage to it, the global situation has not changed and its development remains one of the priorities, especially in the context of Ukraine's vector for European integration. However, in today's conditions, appropriate strategies and tools for their implementation are necessary to preserve and restore the competitiveness of the hospitality industry. The purpose of the article: to justify strategic alternatives for restoring the competitiveness of the hospitality sector of Ukraine Results. The article substantiates that since the field of hospitality is a complex socio-ecological-economic system, which is characterized by significant regional differences, it is advisable to apply combined strategic sets formed on the basis of a hierarchical approach. The application of three levels of strategic alternatives is substantiated: Level I as a market positioning strategy (globalization, deep market penetration, adaptation, anticipatory development); Level II as strategic directions for ensuring competitive advantages (creating new competitive advantages, increasing competitive advantages, maintaining a competitive position, restoring lost competitive advantages); Level III as typical competitive strategies (diversification, differentiation, focus, specialization, cost leadership). The results of the study were used to justify the correlation of the specified strategies with the identified trends in the development of the hospitality industry in the world and in Ukraine. The sets of alternative strategies will be identified in the coordinates "Level of competitive advantages" / "Level of competitiveness", according to which the regions of Ukraine will be grouped and the specifics of the implementation of each of the sets will be determined. In the conditions of the current situation, the proposals are characterized by a high level of speculation, but they can serve as a reference point for the development of the hospitality industry in the regions of Ukraine, the basis of regional programs and strategies, which is a perspective for further research. Conclusions. A strategic approach to restoring the competitiveness of the hospitality sector of Ukraine ensures the prediction and achievement of expected results, obtaining competitive advantages for the long-term perspective, is the basis for the development of regional strategies and programs, which is of practical importance.

Intratumoral lactic acid neutralization strategy for boosting chemoimmunotherapy using liposomal sodium bicarbonate

Glycolysis-related lactic acid overproduction creates an “ion-trapping” barrier and immunosuppressive tumor microenvironment that compromise effective intratumoral drug delivery and therapy. Therefore, normalization of tumor microenvironment via lactic acid neutralization can be a promising avenue for overcoming this therapeutic hurdle. In this study, the flexible liposomes loaded with sodium bicarbonate (NaHCO3@Flip) were used as a nano-adjuvant to boost chemoimmunotherapy. Their effects on assisting DOXIL and anti-PD-1 therapy were investigated. NaHCO3@Flip achieved deep tumor penetration, with the ability to neutralize lactic acid and normalize the acidic tumor microenvironment. NaHCO3@Flip is biosafe and can enhance cellular uptake efficiency of doxorubicin (DOX) by overcoming the ion-trapping barrier and amplify immunogenic cell death induced by DOX. The combination therapy of liposomal DOX and NaHCO3@Flip demonstrated enhanced inhibition of tumor growth. NaHCO3@Flip can also synergize with PD-1 antibody therapy. NaHCO3@Flip has the potential to serve as a therapeutic adjuvant for boosting chemoimmunotherapy by overcoming the ion-trapping effect and normalizing the tumor microenvironment.

An effective and specific cancer theranostic nanoplatform with NIR-II fluorescence imaging-guided photothermal/chemodynamic therapy

Nanomaterial-based second near-infrared region (NIR-II) fluorescent probes have deep tissue penetration. However, it is limited by low catalytic efficiency and specific recognition in the tumor microenvironment (TME). Herein, Ag2S-Cu(II)-Cu2-xSe diagnostic nanoparticles have been established by Cu2-xSe and Ag2S QDs, which can serve as diagnostic agents. They can improve the precise diagnosis of cancer via a NIR-II imaging-guided multimodal photothermal/chemodynamic therapy strategy under near-infrared (808 nm) light irradiation. Under neutral conditions, the fluorescence of Ag2S-Cu(II)-Cu2-xSe nanoplatforms is in the “off” mode, which is selectively turned on only in the tumor microenvironment. Ag2S-Cu(II)-Cu2-xSe NPs not only emit fluorescence specifically in the TME but also have efficient photothermal conversion properties. Significantly, Ag2S-Cu(II)-Cu2-xSe has experimentally demonstrated a strong combined therapeutic effect and can consume excess intracellular glutathione (GSH) through redox reactions. This work presents an effective strategy for achieving precise and safe multifunctional nanodiagnostic platforms.

Stromal Reprogramming Optimizes KRAS-Specific Chemotherapy Inducing Antitumor Immunity in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer and is often characterized with rich stroma and mutated KRAS, which determines the tumor microenvironment (TME) and therapy response. Turning immunologically "cold" PDAC into "hot" is an unmet need to improve the therapeutic outcome. Herein, we propose a programmable strategy by sequential delivery of pirfenidone (PFD) and nanoengineered KRAS specific inhibitor (AMG510) and gemcitabine (GEM) liposomes. PFD could achieve precise reduction of the extracellular matrix (ECM) by reprogramming pancreatic stellate cells (PSCs). Subsequently, targeting the KRAS-directed oncogenic signaling pathway effectively inhibited tumor proliferation and migration, which sensitized a chemotherapeutic drug and promoted immunogenic cell death (ICD). In preclinical mouse models of PDAC, PFD mediated stromal modulation enhanced the deep penetration of nanoparticles and improved their subsequent performance in tumor growth inhibition. The molecular mechanisms elucidated that the stroma intervention and KRAS signal pathway regulation reshaped the immunosuppression of PDAC and optimized cytotoxic T-cell-mediated antitumor immunity with sustained antitumor memory. Overall, our study provides a practical strategy with clinical translational promise for immunologically cold tumor PDAC treatment.

Hyperglycemia Targeting Nanomotors for Accelerated Healing of Diabetic Wounds by Efficient Microenvironment Remodeling

AbstractMultifunctional nanoagents are robust to remodel environments for managing chronic diabetic wounds. However, their delivery primarily relies on Brownian motion and randomly enhanced diffusion. Here, taking advantage of wound heterogeneity, such as the uneven distribution of glucose, hyperglycemia targeting nanomotors are proposed. They are capable of efficiently targeting hyperglycemic interfaces in diabetic wounds for significantly accelerating their healing by employing endogenous glucose‐activated cascade reactions and responding to local glucose gradients. Compared to previous counterparts, they show a four‐fold enhancement in effective coverage within 60 s and a multiplied accumulation at hyperglycemic interfaces, facilitating deep penetration. Correspondingly, the downregulation of glucose levels is apparently enhanced, while pH‐lowering and oxygen‐supplying are both improved. In comparison to the counterparts delivered by passive diffusion and randomly enhanced diffusion, the hyperglycemia targeting nanomotor‐based spray accelerates the wound healing upon diabetic mice by approximately 30% and 23%, resulting from the restricted inflammatory response, effective reactive oxygen species (ROS) scavenging and elevated vascular endothelial growth factor levels (VEGF). This study presents a generally efficient approach to facilitating the targeted delivery of nanoagents for the effective management of diabetic wounds by utilizing wound heterogeneity, which can be extended to other therapeutic systems.

Trapping light, revealing properties: Laser trapping as a powerful tool for photoluminescence spectroscopy

Laser trapping, a non-contact technique for manipulating microscopic objects, has gained prominence in scientific research. When coupled with fluorescence spectroscopy, it offers a powerful tool for exploring material properties. This study demonstrates the application of laser trapping in the crystallization of MAPbBr3 perovskites and its simultaneous use for photoluminescence imaging. MAPbBr3 perovskites are a class of materials with exceptional optical properties, making them attractive for various optoelectronic applications. However, conventional excitation methods using UV light can lead to phase segregation and mechanical distortion of these materials. Two-photon excitation, on the other hand, offers advantages such as deeper penetration and reduced scattering interference. In this research, we utilize a 1064 nm continuous wave laser for both trapping and excitation purposes. The MAPbBr3 perovskite, with its absorption band ranging from 400 to 540 nm, exhibits two-photon excitation at 532 nm. By focusing the laser beam at the air-solution interface, we successfully crystallize MAPbBr3 perovskites from an unsaturated precursor solution. Simultaneously, the same laser source is used for photoluminescence imaging, allowing for real-time analysis of the crystal's emission properties. This approach eliminates the need for additional excitation sources and simplifies the experimental setup. The combination of laser trapping and two-photon excitation opens up new possibilities for studying perovskite materials. It provides a gentle and non-invasive method for manipulating and characterizing hybrid perovskites materials, paving the way for advancements in various fields such as optoelectronics and energy harvesting.

Microsoft's Strategic Advantage: An In-depth Analysis Based on Porter's Five Forces Model

Abstract: This article uses Michael Porter's five forces model to analyze Microsoft's competitive situation in the global technology industry. It emphasizes that Microsoft has maintained its industry leadership by continuously innovating its technology and being keenly aware of market changes. The analysis covers Microsoft's strategies in facing market competition, the threat of new entrants, the challenge of substitute products, the bargaining power of suppliers and buyers, and its impact on the company's performance. The study pointed out that Microsoft has established high barriers to entry in its main business areas, thereby effectively preventing the entry of new competitors. The article also analyzes how Microsoft maintains its competitive advantage and market leadership through product differentiation, innovation, flexible pricing strategies, and the ability to adapt to market structure. Although Microsoft faces many challenges, it has successfully maintained its competitiveness in the global market through solid R&D capabilities, an extensive product portfolio, deep market penetration, and an active response to changes globally.

Biodegradable ICG-Conjugated Germanium Nanoparticles for In Vivo Near-Infrared Dual-Modality Imaging and Photothermal Therapy.

Theranostics, by integrating diagnosis and therapy on a single platform, enables real-time monitoring of tumors during treatment. To improve the accuracy of tumor diagnosis, the fluorescence and photoacoustic imaging modalities can complement each other to achieve high resolution and a deep penetration depth. Despite the superior performance, the biodegradability of theranostic agents plays a critical role in enhancing nanoparticle excretion and reducing chronic toxicity, which is essential for clinical applications. Herein, we synthesize biocompatible and biodegradable indocyanine green (ICG)-conjugated germanium nanoparticles (GeNPs) and investigate their biodistributions in nude mice and 4T1 tumor models after intravenous injections using near-infrared (NIR) dual-modality fluorescence and photoacoustic imaging. The ICG-conjugated GeNPs have strong NIR absorption due to the NIR-absorbing ICG and Ge in combination, emit strong NIR fluorescence due to the multilayered ICG coatings, and exhibit very low in vitro and in vivo toxicity. After tail vein injections, the ICG-conjugated GeNPs mainly accumulate in the liver and spleen as well as the tumor with the help of the enhanced permeability and retention effect. The tumor's fluorescence signal is much stronger than that of the control group injected with pure ICG solution, as the GeNPs can function as biodegradable carriers for efficiently delivering the ICG molecules to the tumor. Lastly, the ICG-conjugated GeNPs accumulated in the tumor can also be utilized for photothermal treatment under NIR laser irradiation, after which the tumor volume almost diminishes after 14 days. The experimental findings in this work demonstrate that the ICG-conjugated GeNPs are promising theranostic agents with exceptional biodegradability for in vivo NIR dual-modality imaging and photothermal therapy.

Engineering Stimuli-Responsive Materials for Precision Medicine.

Over the past decade, precision medicine has garnered increasing attention, making significant strides in discovering new therapeutic drugs and mechanisms, resulting in notable achievements in symptom alleviation, pain reduction, and extended survival rates. However, the limited target specificity of primary drugs and inter-individual differences have often necessitated high-dosage strategies, leading to challenges such as restricted deep tissue penetration rates and systemic side effects. Material science advancements present a promising avenue for these issues. By leveraging the distinct internal features of diseased regions and the application of specific external stimuli, responsive materials can be tailored to achieve targeted delivery, controllable release, and specific biochemical reactions. This review aims to highlight the latest advancements in stimuli-responsive materials and their potential in precision medicine. Initially, we introduce disease-related internal stimuli and capable external stimuli, elucidating the reaction principles of responsive functional groups. Subsequently, we provide a detailed analysis of representative pre-clinical achievements of stimuli responsive materials across various clinical applications, including enhancements in the treatment of cancers, injury diseases, inflammatory diseases, infection diseases, and high-throughput microfluidic biosensors. Finally, we discuss some clinical challenges, such as off-target effects, long-term impacts of nano-materials, potential ethical concerns, and offer insights into future perspectives of stimuli-responsive materials.

Comparative Validation of Scintillator Materials for X-Ray-Mediated Neuronal Control in the Deep Brain

When exposed to X-rays, scintillators emit visible luminescence. X-ray-mediated optogenetics employs scintillators for remotely activating light-sensitive proteins in biological tissue through X-ray irradiation. This approach offers advantages over traditional optogenetics, allowing for deeper tissue penetration and wireless control. Here, we assessed the short-term safety and efficacy of candidate scintillator materials for neuronal control. Our analyses revealed that lead-free halide scintillators, such as Cs3Cu2I5, exhibited significant cytotoxicity within 24 h and induced neuroinflammatory effects when injected into the mouse brain. In contrast, cerium-doped gadolinium aluminum gallium garnet (Ce:GAGG) nanoparticles showed no detectable cytotoxicity within the same period, and injection into the mouse brain did not lead to observable neuroinflammation over four weeks. Electrophysiological recordings in the cerebral cortex of awake mice showed that X-ray-induced radioluminescence from Ce:GAGG nanoparticles reliably activated 45% of the neuronal population surrounding the implanted particles, a significantly higher activation rate than europium-doped GAGG (Eu:GAGG) microparticles, which activated only 10% of neurons. Furthermore, we established the cell-type specificity of this technique by using Ce:GAGG nanoparticles to selectively stimulate midbrain dopamine neurons. This technique was applied to freely behaving mice, allowing for wireless modulation of place preference behavior mediated by midbrain dopamine neurons. These findings highlight the unique suitability of Ce:GAGG nanoparticles for X-ray-mediated optogenetics. The deep tissue penetration, short-term safety, wireless neuronal control, and cell-type specificity of this system offer exciting possibilities for diverse neuroscience applications and therapeutic interventions.

Short-Wave Infrared Upconverting Nanoparticles.

Optical technologies enable real-time, noninvasive analysis of complex systems but are limited to discrete regions of the optical spectrum. While wavelengths in the short-wave infrared (SWIR) window (typically, 1700-3000 nm) should enable deep subsurface penetration and reduced photodamage, there are few luminescent probes that can be excited in this region. Here, we report the discovery of lanthanide-based upconverting nanoparticles (UCNPs) that efficiently convert 1740 or 1950 nm excitation to wavelengths compatible with conventional silicon detectors. Screening of Ln3+ ion combinations by differential rate equation modeling identifies Ho3+/Tm3+ or Tm3+ dopants with strong visible or NIR-I emission following SWIR excitation. Experimental upconverted photoluminescence excitation (U-PLE) spectra find that 10% Tm3+-doped NaYF4 core/shell UCNPs have the strongest 800 nm emission from SWIR wavelengths, while UCNPs with an added 2% or 10% Ho3+ show the strongest red emission when excited at 1740 or 1950 nm. Mechanistic modeling shows that addition of a low percentage of Ho3+ to Tm3+-doped UCNPs shifts their emission from 800 to 652 nm by acting as a hub of efficient SWIR energy acceptance and redistribution up to visible emission manifolds. Parallel experimental and computational analysis shows rate equation models are able to predict compositions for specific wavelengths of both excitation and emission. These SWIR-responsive probes open a new IR bioimaging window, and are responsive at wavelengths important for vision technologies.

Single-atom nanozyme liposome-integrated microneedles for in situ drug delivery and anti-inflammatory therapy in Parkinson’s disease

Treatment for Parkinson’s disease (PD) has been impeded by inefficient treatment results and multiple membrane barriers during drug delivery. This study reports the design, synthesis, and application of microneedles (MNs) loaded with mitochondrion-targeted liposome encapsulated iron (Fe)-isolated single-atom nanozymes (Mito@Fe-ISAzyme, MFeI), called MFeI MNs, for in situ drug delivery into the brain parenchyma and efficient enrichment of drugs in lesion sites. In in vitro experiments, MFeI can scavenge reactive oxygen species (ROS) and protect the neurons via mitochondrial targeting, guaranteeing the subsequent treatment of PD. Using PD mouse models, we compared the intravenous injection of MFeI with the brain in situ administration of MFeI MNs (in situ MFeI MNs). Results showed that in situ MFeI MNs significantly improved the deep penetration of the drug into brain parenchyma, especially in the vital pathological sites such as the substantia nigra pars compacta and striatum. Importantly, ROS elimination and neuroinflammatory remission in the lesion site were observed, thereby efficiently alleviating the behavioral disorders and pathological symptoms of PD mice. Therefore, the MNs system for in situ single-atom nanozyme liposome delivery exhibits great potential in PD treatment.Graphical abstract

A highly permeable nanoplatform based on functionalized carbon dots for synergistic reactive oxygen/nitrogen species tumor therapy

Reactive oxygen species (ROS)-based antitumor strategies, particularly chemodynamic therapy, have garnered considerable attention. However, challenges such as difficulties in achieving deep penetration, relatively low H2O2 levels in the tumor microenvironment, the requirement for low pH by the Fenton reaction, and their short lifespan have impeded satisfactory therapeutic outcomes. Hence, we have developed a nanoplatform with enhanced permeability that not only generates significant amounts of ROS but also converts them into longer-lasting reactive nitrogen species (RNS), thereby improving tumor therapy efficacy. In our study, carbon dots were functionalized by doping with gold atoms and grafting nitrosoglutathione (GSNO) to form ACN, which exhibits glucose oxidase-like properties and enables laser-responsive NO release. ACN and indocyanine green (ICG) were then loaded onto MnO2 nanoflowers to form MnO2@AI. Upon arrival at the tumor site, MnO2 reacts with H2O2 and GSH, leading to its degradation and the subsequent release of ACN, which is characterized by three permeation-promoting properties: ultra-small size, positive charge, and NO content. In addition, ACN promotes H2O2 production through glucose metabolism and reduces pH, both of which enhance the Fenton-like reaction of MnO2, thereby amplifying ROS generation. The ICG in MnO2@AI enhances its photothermal properties, leading to the responsive release of NO from GSNO grafted onto ACN, which then reacts with the increased ROS to generate more toxic RNS. Collectively, the approach described herein offers substantial potential for advancing the treatment of malignant tumors.