Deep Penetration Research Articles

NIR-II-Responsive Hybrid System Achieves Cascade-Augmented Antitumor Immunity via Genetic Engineering of Both Bacteria and Tumor Cells.

The combination of nanoparticles and tumor-targeting bacteria for cancer immunotherapy can overcome the shortcomings of poor nanoparticle accumulation, limited penetration, and restricted distribution. However, it remains a great challenge for the hybrid system to improve therapeutic efficacy through the simultaneous and controllable regulation of immune cells and tumor cells. Herein, a hybrid therapeutic platform is rationally designed to achieve immune cascade-augmented cancer immunotherapy. To construct the hybrids, photothermal nanoparticles responsive to light in the second near-infrared (NIR-II) region are conjugated onto the surface of engineered bacteria through pH-responsive Schiff base bonds. Taking advantage of the hypoxia targeting and deep penetration characteristics of the bacteria, the hybrids can accumulate at tumor sites. Then nanoparticles detach from the bacteria to realize genetic engineering of tumor cells, which induces tumor cell apoptosis and down-regulate the expression of programmed cell death ligand 1 to alleviate immunosuppressive tumor microenvironment. The mild photothermal heating can not only induce tumor-associated antigen release, but also trigger sustainable expression of cytokine interleukin-2. Notably, a synergistic antitumor effect is achieved between the process of p53 transfection and NIR-II light-activated genetic engineering of bacteria. This work proposes a facile strategy for the construction of hybrid system to achieve cascade-augmented cancer immunotherapy.

NIR‐II AIEgens for Infectious Diseases Phototheranostics

Pathogenic infectious diseases have persistently posed significant threats to public health. Phototheranostics, which combines the functions of diagnostic imaging and therapy, presents an extremely promising solution to block the spread of pathogens as well as the outbreak of epidemics owing to its merits of a wide‐spectrum of activity, high controllability, non‐invasiveness, and difficult to acquire resistance. Among multifarious phototheranostic agents, second near‐infrared (NIR‐II, 1000–1700 nm) aggregation‐induced emission luminogens (AIEgens) are notable by virtue of their deep penetration depth, excellent biocompatibility, balanced radiative and nonradiative decay and aggregation‐enhanced theranostic performance, making them an ideal option for combating pathogens. This minireview provides a systematical summary of the latest advancements in NIR‐II AIEgens with emphasis on the molecular design and nanoplatform formulation to fulfill high‐efficiency in treating bacterial and viral pathogens, classified by disease models. Then, the current challenges, potential opportunities, and future research directions are presented to facilitate the further progress of this emerging field.

NIR-II AIEgens for Infectious Diseases Phototheranostics.

Pathogenic infectious diseases have persistently posed significant threats to public health. Phototheranostics, which combines the functions of diagnostic imaging and therapy, presents an extremely promising solution to block the spread of pathogens as well as the outbreak of epidemics owing to its merits of a wide-spectrum of activity, high controllability, non-invasiveness, and difficult to acquire resistance. Among multifarious phototheranostic agents, second near-infrared (NIR-II, 1000-1700 nm) aggregation-induced emission luminogens (AIEgens) are notable by virtue of their deep penetration depth, excellent biocompatibility, balanced radiative and nonradiative decay and aggregation-enhanced theranostic performance, making them an ideal option for combating pathogens. This minireview provides a systematical summary of the latest advancements in NIR-II AIEgens with emphasis on the molecular design and nanoplatform formulation to fulfill high-efficiency in treating bacterial and viral pathogens, classified by disease models. Then, the current challenges, potential opportunities, and future research directions are presented to facilitate the further progress of this emerging field.

Fluorescence and photoacoustic (FL/PA) dual-modal probe: Responsive to reactive oxygen species (ROS) for atherosclerotic plaque imaging

Accurate and early detection of atherosclerosis (AS) is imperative for their effective treatment. However, fluorescence probes for efficient diagnosis of AS often encounter insufficient deep tissue penetration, which hinders the reliable assessment of plaque vulnerability. In this work, a reactive oxygen species (ROS) activated near-infrared (NIR) fluorescence and photoacoustic (FL/PA) dual model probe TPA-QO-B is developed by conjugating two chromophores (TPA-QI and O–OH) and ROS-specific group phenylboronic acid ester. The incorporation of ROS-specific group not only induces blue shift in absorbance, but also inhibits the ICT process of TPA-QO-OH, resulting an ignorable initial FL/PA signal. ROS triggers the convertion of TPA-QO-B to TPA-QO-OH, resulting in the concurrent amplification of FL/PA signal. The exceptional selectivity of TPA-QO-B towards ROS makes it effectively distinguish AS mice from the healthy. The NIR emission can achieve a tissue penetration imaging depth of 0.3 cm. Moreover, its PA775 signal possesses the capability to penetrate tissues up to a thickness of 0.8 cm, ensuring deep in vivo imaging of AS model mice in early stage. The ROS-triggered FL/PA dual signal amplification strategy improves the accuracy and addresses the deep tissue penetration problem simultaneously, providing a promising tool for in vivo tracking biomarkers in life science and preclinical applications.

Thrombin and NIR dual-responsive system driven by heat-gas for thrombus targeted therapy

Drug thrombolysis is the main means of clinical treatment for thrombotic-related diseases. However, serious bleeding complications caused by low drug delivery efficiency and secondary vascular embolism usually lead to unsatisfactory therapeutic effects. Herein, we constructed a thrombin and near-infrared (NIR) dual-responsive drug-loaded intelligent system to solve the above problems. The CREKA-modified polydopamine (PDA) nanoparticles (NPs) were crosslinked by thrombin-responsive peptide (Pep), to obtain Pep-PPC nanocarriers with special mesoporous nanostructures. Subsequently, NO donor BNN6 and thrombolytic drug UK were loaded on the surface and into the mesoporous of Pep-PPC, to get the multifunctional Pep-NO@PPC/UK. In vitro and in vivo results proved that Pep-NO@PPC/UK could effectively recognize and aggregate at the thrombus site via CREKA-mediated active targeting. Then local abundant thrombin cleaved the nanoplatform to release UK. Meanwhile, PDA converted NIR light into heat and synchronously triggered NO release. This transformed the DDS into a “heat-gas” dual propulsion nanomotor in situ, driving deep penetration of UK in thrombus tissue. Under the combined action of UK and PTT, arterial thrombosis rapidly dissolved with relatively low bleeding risk. More importantly, NO generated in situ could prevent re-embolism of blood vessels at the thrombolytic site by inhibiting activated platelet aggregation, ultimately improving vascular reperfusion rate through a combination of attack and defense mode.

Clovis points and foreshafts under braced weapon compression: Modeling Pleistocene megafauna encounters with a lithic pike.

Historical and ethnographic sources depict use of portable braced shaft weapons, or pikes, in megafauna hunting and defense during Late Holocene millennia in North and South America, Africa, Eurasia and Southeast Asia. Given the predominance of megafauna in Late Pleistocene North America during the centuries when Clovis points appeared and spread across much of the continent (13,050-12,650 cal BP), braced weapons may have been used in hunting of megaherbivores and defense against megacarnivores. Drawing from historical examples of pike use against lions, jaguars, boars, grizzlies, carabao and warhorses we consider the possibility of a fluted lithic pike. Associated osseous rods have been problematic as Clovis foreshafts due to the bevel angle and the apparent weakness of the splint haft when great strength is needed for deep penetration in megafauna hunting. However our review of Late Holocene pike use in megafauna encounters indicates the sharp tip becomes less important after hide or armor has been pierced because compression is sustained. Thus, foreshaft collapse after hide entry may not limit but rather increase the efficacy of the braced weapon. We conduct preliminary static experiments to model a fluted pike that adjusts during compression such that haft collapse and point detachment (when point jams on impact with bone) preserve the fluted biface, beveled rod and wooden mainshaft tip. In addition to Clovis point attributes and association with osseous rods, potential archaeological correlates of Clovis pike use include the high frequency of Clovis point isolates and concentrations of complete points with unbutchered mammoth remains at sites such as Naco in Arizona.

Assessing predator–prey interactions during the Late Triassic of India from bite marks on Hyperodapedon (Archosauromorpha, Rhynchosauria)

ABSTRACT Multiple cranial and mandibular remains of Hyperodapedon huxleyi known from the lower part of the Upper Triassic Maleri Formation were examined to reveal distinct bite marks. These were identified as punctures based on their circular or oval or elliptical outline and deep penetration into the cortical bone, and were found associated with several bone-damaging features such as radiating fractures, serrated boundaries, and collapsed bony surface. In addition, bite traces or drag marks in the form of parallel grooves with U-shaped cross sections are identified. The bite marks are compared with dental morphology of varied Late Triassic carnivores of India, and the probable producers are suggested to be phytosaurs and dinosauriforms. The Maleri trophic structure or food web is reconstructed to reveal interconnectedness between different animal groups, unconfined feeding habits of the animals where the predators were inclined towards opportunistic feeding rather than a niche-based dietary habit. The study highlights the significance of bite marks in the reconstruction of ancient paleoecosystems.

ZnO quantum dots decorated BaTiO3 for cancer sonodynamic therapy

Sonodynamic therapy depending on ultrasound irradiation, which generates reactive species to kill cancer cells, has attracted considerable attention due to the deep tissue penetration depth. However, the insufficient separation of electron/hole pairs induces its limited therapeutic efficiency. Herein, we use oxygen vacancy and ZnO quantum dots decoration techniques to enhance electron/hole separation and reactive species production. In oxygen vacancy-engineered BaTiO3, the higher oxygen vacancy concentration leads to more efficient adsorption of activate O2 and thus results in production of more radicals. In BaTiO3/ZnO heterostructures, the built-in electric field further improves separation of electron/hole pairs. The separated electron/hole react with O2/H2O to produce reactive species of •OH/∙O2- and kill cancer cells upon ultrasound irradiation. The work provides a guidance for sonosensitizers to tumor therapy.

Dynamic polyphenol nanoparticles boost cuproptosis-driven metalloimmunotherapy of breast cancer

Polyphenolic materials have been extensively explored for biomedical applications. However, most polymer-based polyphenols are synthesized by covalently grafting phenol groups on the backbone of polymers and more convenient synthetic strategy remains challenging. Herein, a general and robust strategy to synthesize polypeptide-based polyphenol via selective ortho-hydroxylation of poly(tyrosine) was developed to construct dynamic nanoparticles (GPCuD NPs) composed of Cu2+ and phenylboronic acid modified doxorubicin prodrug (DOX-PBA) via metal-phenol coordination interaction and pH-reversible phenylboronate ester bond, respectively. Furthermore, matrix metalloproteinase-2 (MMP-2)-cleavable GPLGLAG peptide was also included between the polyethylene glycol and polyphenol segments, endowing GPCuD NPs with tumor-specific accumulation and deep penetration through enzyme-triggered depegylation. Notably, Cu2+-chelated nanoparticles efficiently ameliorated the immunosuppressive tumor microenvironment via recruiting antitumor immune cells and repolarizing M2-type tumor-associated macrophages to M1 phenotype. The combination of cuproptosis-driven metalloimmunotherapy with DOX chemotherapy remarkably suppressed 4T1 orthotopic breast tumor growth by 81.9 % and established a long-term immune memory (effective memory T cells up to 30.8 %) to prevent lung metastasis. This study has demonstrated a generalizable polyphenol nanoplatform for tumor-targeted and cuproptosis-regulated combination cancer metalloimmunotherapy.

A near-infrared light-driven Janus nanomotor for deep tumor penetration and enhanced tumor immunotherapy.

A near-infrared light-driven Janus nanomotor is constructed by collagenase-coated gold nanorods and chitosan-functionalized mesoporous organosilica nanoparticles with Mn2+ as the bridging ion. The nanomotors with excellent motility and collagenase activity can potently penetrate into tumors to sufficiently activate innate immune responses, significantly enhancing anti-tumor immune efficacy in vivo.

Curving expectations: The minimal impact of structural curvature in biological puncture mechanics.

Living organisms have evolved various biological puncture tools, such as fangs, stingers, and claws, for prey capture, defense, and other critical biological functions. These tools exhibit diverse morphologies, including a wide range of structural curvatures, from straight cactus spines to crescent-shaped talons found in raptors. While the influence of such curvature on the strength of the tool has been explored, its biomechanical role in puncture performance remains untested. Here, we investigate the effect of curvature on puncture mechanics by integrating experiments with finite element simulations. Our findings reveal that within a wide biologically relevant range, structural curvature has a minimal impact on key metrics of damage initiation or the energies required for deep penetration in isotropic and homogeneous target materials. This unexpected result improves our understanding of the biomechanical pressures driving the morphological diversity of curved puncture tools and provides fundamental insights into the crucial roles of curvature in the biomechanical functions of living puncture systems.

An Integrated Nanoplatform via Dual Channel Excitation for Both Precise Fluorescence Imaging and Photodynamic Therapy of Orthotopic Breast Tumor in NIR-II Region.

Although research on photodynamic therapy (PDT) of malignant tumor has made considerable progress in recent years, it is a remaining challenge to extend PDT to the second near-infrared window (NIR-II) along with real-time and accurate NIR-II fluorescence imaging to determine drug enrichment status and achieve high treatment efficacy. In this work, lanthanide nanoparticles (Ln NPs)-based nanoplatform (LCR) equipped with photosensitizerChlorin e6 (Ce6) and targeting molecular NH2-PEG1000-cRGDfK aredeveloped, which can achieve NIR-II photodynamic therapy (PDT) and NIR-II fluorescence imaging by dual channel excitation. Under 808nm excitation, Nd3+ in the outer layer can absorb the energy and transfer inward to emit strong NIR-II emissions (1064 and 1525nm). Due to the low background noise of NIR-II light and the targeting effect of NH2-PEG1000-cRGDfK, LCR can recognize tiny tumor tissue (≈3mm) and monitor drug distribution in vivo. Under 1530nm excitation, internal Er3+ can be self-sensitized, generating intense upconversion emission (662nm) that can effectively activate Ce6 for in vivo PDT due to the deep tissue penetration of NIR-II light. This study provides a paradigm of theranostic nanoplatform for both real-time fluorescence imaging and PDT of orthotopic breast tumor in NIR-II window.

Amplifying Radiotherapy by Evoking Mitochondrial Oxidative Stress Using a High-performance Aggregation-induced Emission Sonosensitizer.

Developing effective methods to enhance tumor radiosensitivity is crucial for improving the therapeutic efficacy of radiotherapy (RT). Due to its deep tissue penetration, excellent safety profile, and precise controllability, sonosensitizer- based sonodynamic therapy (SDT) has recently garnered significant attention as a promising combined approach with RT. However, the limited reactive oxygen species (ROS) generation ability in the aggregated state and the absence of specific organelle targeting in sonosensitizers hinder their potential to augment RT. This study introduces a fundamental principle guiding the design of high-performance sonosensitizers employed in the aggregated state. Building upon these principles, we develop a mitochondria-targeted sonosensitizer molecule (TCSVP) with aggregation-induced emission (AIE) characteristics by organic synthesis. Then, we demonstrate the abilities of TCSVP to target mitochondria and produce ROS under ultrasound in H460 cancer cells using confocal laser scanning microscopy (CLSM) and fluorescence microscopy. Subsequently, we examine the effectiveness of enhancing tumor radiosensitivity by utilizing TCSVP and ultrasound in both H460 cells and H460 and 4T1 tumor-bearing mice. The results indicate that evoking non-lethal mitochondrial oxidative stress in tumors by TCSVP under ultrasound stimulation can significantly improve tumor radiosensitivity (p <0.05). Additionally, the in vivo safety profile of TCSVP is thoroughly confirmed by histopathological analysis. This work proposes strategies for designing efficient sonosensitizers and underscores that evoking non-lethal mitochondrial oxidative stress is an effective method to enhance tumor radiosensitivity.

Croconaine-based NIR-II fluorescence imaging-guided tumor photothermal therapy induces long-term antitumor immune memory

Photothermal therapy (PTT) for cancers guided by optical imaging has recently shown great potential for precise diagnosis and efficient therapy. The second near-infrared window (NIR-II, 1000–1700 nm) fluorescence imaging (FLI) is highly desirable owing to its good spatial and temporal resolution, deep tissue penetration, and negligible tissue toxicity. Organic small molecules are attractive as imaging and treatment agents in biomedical research because of their low toxicity, fast clearance rate, diverse structures, ease of modification, and excellent biocompatibility. Various organic small molecules have been investigated for biomedical applications. However, there are few reports on the use of croconaine dyes (CRs), especially NIR-II emission CRs. To our knowledge, there have been no prior reports of NIR-II emissive small organic photothermal agents (SOPTAs) based on CRs. Herein, we report a croconaine dye (CR-TPE-T)-based nanoparticle (CR NP) with absorption and fluorescence emission in the NIR-I and NIR-II windows, respectively. The CR NPs exhibited intense NIR absorption, outstanding photothermal properties, and good biological compatibility. In vivo studies showed that CR NPs not only achieved real-time, noninvasive NIR-II FLI of tumors, but also induced significant tumor ablation with laser irradiation guided by imaging, without apparent side effects, and promoted the formation of antitumor immune memory in a colorectal cancer model. In addition, the CR NPs displayed efficient inhibition of breast tumor growth, improved longevity of mice and triggered efficient systemic immune responses, which further inhibited tumor metastasis to the lungs. Our study demonstrates the great potential of CRs as therapeutic agents in the NIR-II region for cancer diagnosis.

Application of radio frequency energy in processing of fruit and vegetable products.

Thermal processing is commonly employed to ensure the quality and extend the shelf-life of fruits and vegetables. Radio frequency (RF) heating has been used as a promising alternative treatment to replace conventional thermal processing methods with advantages of rapid, volumetric, and deep penetration heating characteristics. This article provides comprehensive information regarding RF heating uniformity and applications in processing of fruit and vegetable products, including disinfestation, blanching, drying, and pasteurization. The dielectric properties of fruits and vegetables and their products have also been summarized. In addition, recommendations for future research on RF heating are proposed to enhance practical applications for fruits and vegetables processing in future.

Tribovoltaic Effect Strengthened Microwave Catalytic Antibacterial Composite Hydrogel.

Microwave (MW) therapy is an emerging therapy with high efficiency and deep penetration to combat the crisis of bacterial resistance. However, as the energy of MW is too low to induce electron transition, the mechanism of MW catalytic effect remains ambiguous. Herein, a cerium-based metal-organic framework (MOF) is fabricated and used in MW therapy. The MW-catalytic performance of CeTCPP is largely dependent on the ions in the liquid environment, and the electron transition is achieved through a "tribovoltaic effect" between water molecules and CeTCPP. By this way, CeTCPP can generate reactive oxygen species (ROS) in saline under pulsed MW irradiation, showing 99.9995 ± 0.0002% antibacterial ratio against Staphylococcus aureus (S. aureus) upon two cycles of MW irradiation. Bacterial metabolomics further demonstrates that the diffusion of ROS into bacteria led to the bacterial metabolic disorders. The bacteria are finally killed due to "amino acid starvation". In order to improve the applicability of CeTCPP, It is incorporated into alginate-based hydrogel, which maintains good MW catalytic antibacterial efficiency and also good biocompatibility. Therefore, this work provides a comprehensive instruction of using CeTCPP in MW therapy, from mechanism to application. This work also provides new perspectives for the design of antibacterial composite hydrogel.

Sialidase-Chimeric Bioengineered Bacteria for Tumor-Sialoglycan-Triggered Solid Tumor Therapy.

Adoptive cell therapies for solid tumors are usually limited by off-target antigens, incapable tissue infiltration, and cell function exhaustion. In contrast, bacterial cells possess the inherent competencies of preferential tumor targeting, deep tissue penetration, and high intratumoral bioactivity and represent promising alternatives to overcome these challenges. Here, a sialic-acid-responsive regulatory gene circuit is engineered into Escherichia coli MG1655 to express cytolysin of hemolysin E (HlyE). Furthermore, sialidases are bioorthogonally decorated onto the surface of azido-functionalized bioengineered bacteria for recognizing tumor sialoglycans and cleaving their sialosides into free sialic acids. As chemical inducers, sialic acids feedbackingly activate the bacterial gene circuit to produce HlyE and lyse tumor cells. This study mimics the tumor antigen-induced cytotoxin production and cell lysis that occurs in chimeric antigen receptor T (CAR-T) cells yet surmounts the intrinsic limitations of adoptive cell therapies. Moreover, sialidase-mediated tumor cell desialylation also reverses the immunosuppressive effect of glycoimmune checkpoints and further improves the therapeutic effect of solid tumors.

Machine learning-based in-process monitoring for laser deep penetration welding: A survey

In-process monitoring (IPM) of laser deep penetration welding (LDPW) has witnessed a rapid growth in approaches that embrace machine learning algorithms, utilizing raw sensor input to generate various weld quality evaluations, instead of concentrating on thermomechanical modeling that is hypotheses-driven and hence biased by it. Benefitting from the capability to unravel hidden interactions in the complex laser welding process, numerous data-driven IPM methods have been proposed to address different problems in this area. In this survey, we present a comprehensive analysis of both classical and recent studies, covering the unique physical mechanisms, sensing techniques, methodologies, strengths, and limitations of machine learning-based IPM-LDPW systems. We delve into several critical tasks, including mechanical performance prediction, weld penetration estimation, and weld defects detection. Meanwhile, we explore the latest developments in deep learning and how to incorporate these techniques into IPM systems for LDPW. To inspire future research, we outline unresolved challenges and explore potential opportunities and new perspectives for addressing these challenges.

Detection of Hepatocellular Carcinoma in an Orthotopic Patient-Derived Xenograft with an Epithelial Cell Adhesion Molecule-Specific Peptide.

Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We used phage display methods to biopan against the extra-cellular domain of the purified EpCAM protein, and used IRDye800 as a near-infrared (NIR) fluorophore. The 12-mer sequence HPDMFTRTHSHN was identified, and specific binding to EpCAM was validated with HCC cells in vitro. A binding affinity of kd = 67 nM and onset of k = 0.136 min-1 (7.35 min) were determined. Serum stability was measured with a half-life of T1/2 = 2.6 h. NIR fluorescence images showed peak uptake in vivo by human HCC patient-derived xenograft (PDX) tumors at 1.5 h post-injection. Also, the peptide was able to bind to foci of local and distant metastases in liver and lung. Peptide biodistribution showed high uptake in tumor versus other organs. No signs of acute toxicity were detected during animal necropsy. Immunofluorescence staining of human liver showed specific binding to HCC compared with cirrhosis, adenoma, and normal specimens.

A Small-Molecule NIR-II Probe for the Diagnosis of Hemorrhagic Diseases.

Numerous hemorrhagic disorders, particularly those presenting deep hemorrhage, pose diagnostic challenges, often leading to delayed treatment and severe outcomes. Near-infrared (NIR)-II fluorescence imaging offers advantages such as deep tissue penetration, real-time visualization, and a high signal-to-background ratio, making it highly suitable for diagnosing hemorrhagic diseases. In this study, an NIR-II fluorescent probe LJ-2P carrying carboxylic and phosphoric acid groups is successfully applied for imaging hemorrhagic diseases. LJ-2P demonstrates a strong affinity for fibrinogen and fibrin clots both computationally and experimentally, thus exhibiting increased brightness upon coagulation. As compared to Indocyanine Green, LJ-2P provides a longer imaging window, higher imaging specificity, and signal-to-background ratio, as well as superior photobleaching resistance in three disease models: gastric, pulmonary, and cerebral hemorrhages. These results reveal that LJ-2P demonstrates enhanced imaging capabilities, enabling precise identification of hemorrhagic sites.