Limited Penetration Research Articles

Iron-Reduced Graphene Oxide Core-Shell Micromotors Designed for Magnetic Guidance and Photothermal Therapy under Second Near-Infrared Light.

Core-shell micro/nanomotors have garnered significant interest in biomedicine owing to their versatile task-performing capabilities. However, their effectiveness for photothermal therapy (PTT) still faces challenges because of their poor tumor accumulation, lower light-to-heat conversion, and due to the limited penetration of near-infrared (NIR) light. In this study, we present a novel core-shell micromotor that combines magnetic and photothermal properties. It is synthesized via the template-assisted electrodeposition of iron (Fe) and reduced graphene oxide (rGO) on a microtubular pore-shaped membrane. The resulting Fe-rGO micromotor consists of a core of oval-shaped zero-valent iron nanoparticles with large magnetization. At the same time, the outer layer has a uniform reduced graphene oxide (rGO) topography. Combined, these Fe-rGO core-shell micromotors respond to magnetic forces and near-infrared (NIR) light (1064 nm), achieving a remarkable photothermal conversion efficiency of 78% at a concentration of 434 µg mL-1. They can also carry doxorubicin (DOX) and rapidly release it upon NIR irradiation. Additionally, preliminary results regarding the biocompatibility of these micromotors through in vitro tests on a 3D breast cancer model demonstrate low cytotoxicity and strong accumulation. These promising results suggest that such Fe-rGO core-shell micromotors could hold great potential for combined photothermal therapy.

PACAP glycosides promote cell outgrowth in vitro and reduce infarct size after stroke in a preclinical model

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) is a pleiotropic peptide known to promote many beneficial processes following neural damage and cell death after stroke. Despite PACAP’s known neurotrophic and anti-inflammatory properties, it has not realized its translational potential due to a poor pharmacokinetic profile (non-linear PK/PD), and limited Blood-Brain Barrier Penetration (BBB) permeability. We have previously shown that glycosylation of PACAP increases stability and enhances BBB penetration. In addition, our prior studies showed reduced neuronal cell death and neuroinflammation in models of Parkinson’s disease and Traumatic Brain Injury (TBI). In this study we show that a PACAP(1−27) glucoside retains the known neurotrophic activity of native PACAP(1−27)in vitro and a 5-day daily treatment regimen (100 nM) leads to neurite-like extensions in PC12 cells. In addition, we show that intraperitoneal injection of a PACAP(1−27) lactoside (10 mg/kg) with improved BBB-penetration, given 1-hour after reperfusion in a Transient Middle Cerebral Artery Occlusion (tMCAO) mouse model, reduces the infarct size after the ischemic injury in males significantly by ∼ 36 %, and the data suggest a dose-dependency. In conclusion, our data support further development of PACAP glycopeptides as promising novel drug candidates for the treatment of stroke, an area with an urgent clinical need.

Laser-mediated Solutions: Breaking Barriers in Transdermal Drug Delivery.

Skin diseases pose challenges in treatment due to the skin's complex structure and protective functions. Topical drug delivery has emerged as a preferred method for treating these conditions, offering localized therapy with minimal systemic side effects. However, the skin's barrier properties frequently limit topical treatments' efficacy by preventing drug penetration into deeper skin layers. In recent years, laser-assisted drug delivery (LADD) has gained attention as a promising strategy to overcome these limitations. LADD involves using lasers to create microchannels in the skin, facilitating the deposition of drugs and enhancing their penetration into the target tissue. Several lasers, such as fractional CO2, have been tested to see how well they work at delivering drugs. Despite the promising outcomes demonstrated in preclinical and clinical studies, several challenges persist in implementing LADD, including limited penetration depth, potential tissue damage, and the cost of LADD systems.Furthermore, selecting appropriate laser parameters and drug formulations is crucial to ensuring optimal therapeutic outcomes. Nevertheless, LADD holds significant potential for improving treatment efficacy for various skin conditions, including skin cancers, scars, and dermatological disorders. Future research efforts should focus on optimizing LADD techniques, addressing safety concerns, and exploring novel drug formulations to maximize the therapeutic benefits of this innovative approach. With continued advancements in laser technology and pharmaceutical science, LADD has the potential to revolutionize the field of dermatology and enhance patient care.

EPEN-18. MULTI-OMICS APPROACH REVEALED A TIGHT BLOOD-BRAIN BARRIER IN EPENDYMOMA

Abstract BACKGROUND A major challenge in the treatment of brain tumors is the limited penetration of many drugs through the blood-brain barrier (BBB). BBB characteristics include endothelial cells connected by tight junction proteins (e.g. Claudin5, ZO1, occludin) and the expression of efflux transporters (e.g. P-gp) with the physiological role to limit the accumulation of potentially toxic substances in brain tissue. Our study aims to enhance our understanding of the BBB composition across different molecular groups of ependymoma (EPN) with the goal of leveraging this knowledge to improve therapeutic strategies against these tumors. METHODS We applied a multi-omics approach integrating single-nuclear RNA sequencing and ultra-high content imaging to unravel BBB composition at both transcriptomic and proteomic levels. Patient-derived xenograft (PDX) models were utilized to explore differences in BBB penetration between tumor and healthy brain tissue following drug treatments. RESULTS Expression of tight junction and transporter proteins revealed strong dependencies specific to molecular groups, but were independent of the corresponding brain regions. Human tissue of ST-EPN-ZFTA exhibited highest expression of claudin5, while both ST-EPN-ZFTA and PF-EPN-A represented upregulation of occludin and ZO1 in comparison to healthy tissue. These findings on claudin5 and ZO1 were further confirmed in PDX models. Single-cell data analysis from patients localized the expression of relevant BBB factors to tumor-associated endothelial cells. Treatment of PDX models with drugs revealed disparities in drug penetration between EPN tumors and healthy brain regions. Notably, for most drugs BBB penetration was lower in ST-EPN-ZFTA tumors than healthy brain region. CONCLUSIONS Molecular BBB specifics may contribute to drug resistance of aggressive EPN particularly in ST-EPN-ZFTA tumors, which presented high tight junction expressions and lower drug penetration. This resource aims to improve BBB penetration prediction in EPN, to identify combination therapies targeting BBB components and to select innovative drug delivery approaches.

Geological and geochemical characterization of caprock integrity in the Athabasca oilsands region

Caprocks play a pivotal role in petroleum systems for the accumulation of oil and gas, as well as in processes such as steam injection for heavy oil recovery and geological storage of CO2. In this study, the geological and geochemical characteristics of the caprock from the Cretaceous Wabiskaw Member (Mbr.) and overlying Clearwater Formation (Fm.), situated above the Athabasca oil sand region, were thoroughly examined using core samples obtained from well 1-22-90-14W4. Through HAWK programmed pyrolysis and solvent extraction, the caprock succession was revealed to exhibit limited organic content with total organic carbon content < 2.0 wt% and extractable organic matter (EOM) < 200 ppm. Further analysis using gas chromatography-flame ionization detector and gas chromatography-mass spectrometry on EOM unveiled insights into the mixing dynamics between the underlying oil reservoir and the caprock indigenous materials. Distinct trends in the ratios of low molecular weight (LMW) aromatic hydrocarbons, N-shielded carbazole, benzo[c]carbazole, and concentrations of carbazoles and benzocarbazoles were evident within a 5-m distance from the caprock-reservoir contact, indicating significant fractionation among compounds. Enrichment of these compounds was observed in the shale of the Wabiskaw Mbr., with a reversal of trends occurring within the initial 5 m into the overlying shale of the Clearwater Fm., suggesting limited oil penetration into the shale. The main Clearwater Fm. caprock succession was characterized by a dominance of immature, indigenous terrigenous organic matter, along with background concentrations of carbazole and benzocarbazole and an absence of N-shielded and/or LMW compound preferences. This composition starkly differed from the oil found in the underlying reservoir. The presence of calcareous cements in the Clearwater Fm. shale, approximately 5 m above the base, characterized by high bulk density (with 62% siderite), low porosity, and matrix permeability, contributed significantly to enhancing the sealing capacity of the caprock. The overall results provide compelling evidence that vertical oil leakage from the McMurray Fm. reservoir through the overlying shale of the Clearwater Fm. has not occurred during the post-lithification history with exception of the lower-most 5 m. The clay-rich argillaceous units identified in this study emerge as potential candidates for serving as effective caprock seals for steam injection and CO2 storage.

Advances in Vascular Diagnostics using Magnetic Particle Imaging (MPI) for Blood Circulation Assessment.

Rapid and accurate assessment of conditions characterized by altered blood flow, cardiac blood pooling, or internal bleeding is crucial for diagnosing and treating various clinical conditions. While widely used imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound offer unique diagnostic advantages, they fall short for specific indications due to limited penetration depth and prolonged acquisition times. Magnetic particle imaging (MPI), an emerging tracer-based technique, holds promise for blood circulation assessments, potentially overcoming existing limitations with reduction in background signals and high temporal and spatial resolution, below the millimeter scale. Successful imaging of blood pooling and impaired flow necessitates tracers with diverse circulation half-lives optimized for MPI signal generation. Recent MPI tracers show potential in imaging cardiovascular complications, vascular perforations, ischemia, and stroke. The impressive temporal resolution and penetration depth also position MPI as an excellent modality for real-time vessel perfusion imaging via functional MPI (fMPI). This review summarizes advancements in optimized MPI tracers for imaging blood circulation and analyzes the current state of pre-clinical applications. This work discusses perspectives on standardization required to transition MPI from a research endeavor to clinical implementation and explore additional clinical indications that may benefit from the unique capabilities of MPI.

“Butterfly-effect” nano-platforms for cascade immune amplification and tumor clearance through multi-modal therapy and immune sensitization

Combined dynamic tumor therapy of photodynamic therapy (PDT), sonodynamic therapy (SDT) and microwave dynamic therapy (MDT) can overcome the limitations of single reactive oxygen species (ROS)-based therapy (including limited tissue penetration depth and low ROS production). However, changes in the tumor microenvironment caused by ROS amplification and oxygen depletion induce severe immunosuppression at the tumor site, indicating effective immunosensitization of the tumors are urgently needed. Here, melanin-hematoporphyrin-chloroquine R837-hyaluronic acid (MHRH) nanoplatform that can simultaneously respond to 980 nm laser /1064 nm laser/ultrasonic/microwave was prepared for PDT/SDT/MDT, achieving outbreak of ROS in deep tumor. More importantly, the photothermal ablation and the participation of chloroquine R837 of MHRH NPs reversed the immunosuppression caused by oxygen depletion after ROS outbreak by promoting DCs maturation and secretion of macrophage exosomes. In summary, the natural MHRH nano-platform supplies an obvious anti-tumor “butterfly effect” through ROS outbreak, thermal ablation and significant immunosuppressive reversal, which provides a new and promising combined strategy of ROS-dynamic therapy and immune agonists in deep tumor tissues.

An implantable piezoelectric ultrasound stimulator (ImPULS) for deep brain activation

Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO3]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.

Photobiomodulation Therapy on Brain: Pioneering an Innovative Approach to Revolutionize Cognitive Dynamics.

Photobiomodulation (PBM) therapy on the brain employs red to near-infrared (NIR) light to treat various neurological and psychological disorders. The mechanism involves the activation of cytochrome c oxidase in the mitochondrial respiratory chain, thereby enhancing ATP synthesis. Additionally, light absorption by ion channels triggers the release of calcium ions, instigating the activation of transcription factors and subsequent gene expression. This cascade of events not only augments neuronal metabolic capacity but also orchestrates anti-oxidant, anti-inflammatory, and anti-apoptotic responses, fostering neurogenesis and synaptogenesis. It shows promise for treating conditions like dementia, stroke, brain trauma, Parkinson's disease, and depression, even enhancing cognitive functions in healthy individuals and eliciting growing interest within the medical community. However, delivering sufficient light to the brain through transcranial approaches poses a significant challenge due to its limited penetration into tissue, prompting an exploration of alternative delivery methods such as intracranial and intranasal approaches. This comprehensive review aims to explore the mechanisms through which PBM exerts its effects on the brain and provide a summary of notable preclinical investigations and clinical trials conducted on various brain disorders, highlighting PBM's potential as a therapeutic modality capable of effectively impeding disease progression within the organism-a task often elusive with conventional pharmacological interventions.

Cranial ultrasound in preterm infants ≤ 32 weeks gestation—novel insights from the use of very high-frequency (18-5 MHz) transducers: a case series

The quality of cranial ultrasound has improved over time, with advancing technology leading to higher resolution, faster image processing, digital display, and back-up. However, some brain lesions may remain difficult to characterize: since higher frequencies result in greater spatial resolution, the use of additional transducers may overcome some of these limitations. The very high-frequency transducers (18-5 MHz) are currently employed for small parts and lung ultrasound. Here we report the first case series comparing the very high-frequency probes (18-5 MHz) with standard micro-convex probes (8-5 MHz) for cranial ultrasound in preterm infants. In this case series, we compared cranial ultrasound images obtained with a micro-convex transducer (8-5 MHz) and those obtained with a very high-frequency (18-5 MHz) linear array transducer in 13 preterm infants ≤ 32 weeks gestation (9 with cerebral abnormalities and 4 with normal findings). Ultrasound examinations using the very high-frequency linear transducer and the standard medium-frequency micro-convex transducer were performed simultaneously. We also compared ultrasound findings with brain MRI images obtained at term corrected age. Ultrasound images obtained with the very high-frequency (18-5 MHz) transducer showed high quality and accuracy. Notably, despite their higher frequency and expected limited penetration capacity, brain size is small enough in preterm infants, so that brain structures are close to the transducer, allowing for complete evaluation. Conclusion: We propose the routine use of very high-frequency linear probes as a complementary scanning modality for cranial ultrasound in preterm infants ≤ 32 weeks gestation.What is Known:• Brain lesions in preterm infants may remain insufficiently defined through conventional cranial ultrasound scan.• Higher frequency probes offer better spatial resolution but have a narrower filed of exploration and limited penetration capacity.What is New:• Very high-frequency probes were compared with standard medium-frequency probes for cranial ultrasound in infants ≤ 32 weeks' gestation.• Thanks to the smaller skull size of preterm infants, the new very high-frequency transducers allowed a complete and accurate evaluation.

RhoMax: Computational Prediction of Rhodopsin Absorption Maxima Using Geometric Deep Learning.

Microbial rhodopsins (MRs) are a diverse and abundant family of photoactive membrane proteins that serve as model systems for biophysical techniques. Optogenetics utilizes genetic engineering to insert specialized proteins into specific neurons or brain regions, allowing for manipulation of their activity through light and enabling the mapping and control of specific brain areas in living organisms. The obstacle of optogenetics lies in the fact that light has a limited ability to penetrate biological tissues, particularly blue light in the visible spectrum. Despite this challenge, most optogenetic systems rely on blue light due to the scarcity of red-shifted opsins. Finding additional red-shifted rhodopsins would represent a major breakthrough in overcoming the challenge of limited light penetration in optogenetics. However, determining the wavelength absorption maxima for rhodopsins based on their protein sequence is a significant hurdle. Current experimental methods are time-consuming, while computational methods lack accuracy. The paper introduces a new computational approach called RhoMax that utilizes structure-based geometric deep learning to predict the absorption wavelength of rhodopsins solely based on their sequences. The method takes advantage of AlphaFold2 for accurate modeling of rhodopsin structures. Once trained on a balanced train set, RhoMax rapidly and precisely predicted the maximum absorption wavelength of more than half of the sequences in our test set with an accuracy of 0.03 eV. By leveraging computational methods for absorption maxima determination, we can drastically reduce the time needed for designing new red-shifted microbial rhodopsins, thereby facilitating advances in the field of optogenetics.

Unlocking the potential of protein-derived peptides to target G-quadruplex DNA: from recognition to anticancer activity.

Noncanonical nucleic acid structures, particularly G-quadruplexes, have garnered significant attention as potential therapeutic targets in cancer treatment. Here, the recognition of G-quadruplex DNA by peptides derived from the Rap1 protein is explored, with the aim of developing novel peptide-based G-quadruplex ligands with enhanced selectivity and anticancer activity. Biophysical techniques were employed to assess the interaction of a peptide derived from the G-quadruplex-binding domain of the protein with various biologically relevant G-quadruplex structures. Through alanine scanning mutagenesis, key amino acids crucial for G-quadruplex recognition were identified, leading to the discovery of two peptides with improved G-quadruplex-binding properties. However, despite their in vitro efficacy, these peptides showed limited cell penetration and anticancer activity. To overcome this challenge, cell-penetrating peptide (CPP)-conjugated derivatives were designed, some of which exhibited significant cytotoxic effects on cancer cells. Interestingly, selected CPP-conjugated peptides exerted potent anticancer activity across various tumour types via a G-quadruplex-dependent mechanism. These findings underscore the potential of peptide-based G-quadruplex ligands in cancer therapy and pave the way for the development of novel therapeutic strategies targeting these DNA structures.

Optical Microneedle-Lens Array for Selective Photothermolysis.

Photothermolysis is the process that converts radiation energy into thermal energy, which results in the destruction of surrounding tissues or cells through thermal diffusion. Laser therapy that is based on photothermolysis has been a widely used treatment for various skin diseases such as skin cancers and port-wine stains. It offers several benefits such as non-invasiveness and selective treatment. However, the use of light, e.g., laser, for safe and effective photothermolysis becomes challenging due to the limited penetration of light into skin tissue as well as the presence of melanin, which absorbs this light. To solve the current issues, we propose an optical microneedle-lens array (OMLA) coated with gold in this work to directly deliver light to targeted skin layers without being absorbed by surrounding tissues as well as melanin, which results in the improvement of the efficiency of photothermal therapy. We developed a novel fabrication method, frame-guided micromolding, to prepare the OMLA by assembling two negative molds with simultaneous alignment. In addition, evaluations of the optical and heat transfer characteristics of the OMLA were performed. We expect our developed OMLA to play a crucial role in realizing more effective laser therapy by allowing the precise delivery of photons to the target area.

Electrochemical Characterization of the Encapsulation and Release of 5-Fluorouracil in Nanocarriers Formed from Soy Lecithin Vesicles.

5-Fluorouracil (5-FU) is an antineoplastic agent known for its low bioavailability and limited cellular penetration, often resulting in adverse effects on healthy cells. Thus, finding vehicles that enhance bioavailability, enable controlled release, and mitigate adverse effects is crucial. The study focuses on encapsulating 5-FU within soy lecithin vesicles (SLVs) and assessing its impact on the carrier's properties and functionality. Results show that incorporating 5-FU does not affect SLVs' size or polydispersity, even postlyophilization. Liberation of 5-FU from SLVs requires system disruption rather than spontaneous release, with an encapsulation efficiency of approximately 43% determined using Square Wave Voltammetry. Cytotoxicity assays on colorectal cancer cells reveal SLV-based delivery's significant efficacy, surpassing free drug solution effects with 45% cell viability after 72 h vs 73% viability. The research addresses 5-FU's limited bioavailability by creating a biocompatible nanocarrier for efficient drug delivery, highlighting SLVs as promising for targeted cancer therapy due to sustained antiproliferative effects and improved cellular uptake. The study underscores the importance of tailored drug delivery systems in enhancing therapeutic outcomes and suggests SLV/5-FU formulations as a potential advancement in cancer treatment strategies.

Measuring the Fate and Natural Attenuation Potential of a Viscous Marine Fuel on an Artificial Beach Mesocosm

Shoreline oiling poses a risk to coastal ecosystems and resources. Understanding the natural attenuation potential and impact of different sediment types is important for choosing appropriate intervention strategies and priority areas following a spill. Simulated IFO-40 oil spills on artificial beach mesocosms were carried out using different sediment types: sandy beach and sandy tidal flat, under low energy tidal cycles over a 5-day period. Chemical and biological analysis of leachate and sediment was conducted to understand the movement of oil through these mesocosms. Rapid oil movement from the oil slick to the surface sediment layer was observed in the sandy beach enclosures, while slower oil movement was observed in the sandy tidal flat enclosures. Increased hydrocarbon dissolution was observed in the sandy beach enclosures, marked by higher concentrations of low molecular weight n-Alkanes (C12 − 15) and naphthalenes (C0 − 3) in sandy beach leachate compared to sandy tidal flat samples. Despite the increase in hydrocarbons, there were no major shifts in microbial communities observed in the leachate and sediment compartments for either sediment type. Both prokaryote and microeukaryote communities differed between the two sediment types, with little overlap between dominant sequences. Our results indicate that limited oil penetration occurs within sandy tidal flat shorelines resulting in oil accumulation suggesting that sorbent or vacuuming could be used as emergency response to minimize the environmental and ecological impacts of spilled oil.

Structure-Based Rational Design of Constrained Peptides as TIM-3 Inhibitors.

Blocking the immunosuppressive function of T-cell immunoglobulin mucin-3 (TIM-3) is an established therapeutic strategy to maximize the efficacy of immune checkpoint inhibitors for cancer immunotherapy. Currently, effective inhibition of TIM-3 interactions relies on monoclonal antibodies (mAbs), which come with drawbacks such as immunogenicity risk, limited tumor penetration, and high manufacturing costs. Guided by the X-ray cocrystal structures of TIM-3 with mAbs, we report an in silico structure-based rational design of constrained peptides as potent TIM-3 inhibitors. The top cyclic peptide from our study (P2) binds TIM-3 with a K D value of 166.3 ± 12.1 nM as determined by surface plasmon resonance (SPR) screening. Remarkably, P2 efficiently inhibits key TIM-3 interactions with natural TIM-3 ligands at submicromolar concentrations in a panel of cell-free and cell-based assays. The capacity of P2 to reverse immunosuppression in T-cell/cancer cell cocultures, coupled with favorable in vitro pharmacokinetic properties, highlights the potential of P2 for further evaluation in preclinical models of immuno-oncology.

Nano-sensitizer with self-amplified drug release and hypoxia normalization properties potentiates efficient chemoradiotherapy of pancreatic cancer

The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia—primarily caused by limited oxygen penetration—has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution.

Cryoablation of ventricular tachycardia using ultra-low temperature technology: acute success and insights from the post-interventional CMR

Abstract Background Radiofrequency catheter ablation (RFCA) has good acute and long-term success rates in idiopathic and ischemic ventricular arrhythmia (VA). Drawbacks of the RFCA are reversibility of the edema and limited penetration of the RF energy into the tissue which explain a worse effectiveness in midmyocardial substrates. In comparison to RFCA, the lesions produced by ultra-low temperature cryoablation (ULTC) which uses near-critical nitrogen cryogen at -1960C can be both deeper and irreversible, depending on the duration of the freeze. Purpose We aimed to evaluate the acute effectiveness of a new ULTC technology for VA by examining post-interventional cardiac magnetic resonance images (CMR) with late gadolinium enhancement (LGE), as a part of multi-center Cryocure-VT study. Methods Between December 2022 and May 2023, we ablated 6 patients (age 63±16%; 5 male) with sustained VA and structural heart disease. Three patients had previous myocardial infarction; 1 cardiac sarcoidosis, 1 LMNA/C dilated cardiomyopathy and 1 post-myocarditis VA. LGE-CMR was available in all patients before the ULTC. At first, electro-anatomical mapping and VA induction were performed followed by ULTC using transseptal access. Each application consisted of freeze-thaw-freeze cycle with freeze duration at operator’s discretion based on manufacturer-recommended duration-depth curve. At the end, induction protocol was repeated to assess the acute success. Additionally, LGE-CMR was performed after ablation as an attempt to visualize the cryo-lesions. Results Median of 6 applications (IQR 4.75-7.5) of cryo-energy were applied per patient. Median procedure time was 180 min (IQR 97-180), and median fluoroscopy time of 20 min (IQR 15-26). Septal VA exits were detected in 3/6 patients; in 1 the exit was at aorto-mitral continuity; in 2 – basal inferior. After ablation, no VAs were inducible in 5/6 (83%) patients. The only patient with failure to ablate all VAs had fewer applications (n=4) and shorter freeze duration of 30 sec., as compared to the rest. Post-procedural CMR revealed new LGE with up to 75% transmurality in 5/6 patients; microvascular obstruction in 4/6 patients. Only LV edema, but no LGE was observed in the patient with shortest freeze time, who also had intra-hospital recurrence. No complications occurred. Conclusions Cryoablation of VA using a new ultra-low temperature technology is effective and safe to ablate VT even in patients with mid-septal substrates. New LGE in result of ULTCA can be observed in CMR and the lesions depth depends on the duration of application.

NIR-II Light-Driven Genetically Engineered Exosome Nanocatalysts for Efficient Phototherapy against Glioblastoma.

Glioblastoma (GBM) poses a significant therapeutic challenge due to its invasive nature and limited drug penetration through the blood-brain barrier (BBB). In response, here we present an innovative biomimetic approach involving the development of genetically engineered exosome nanocatalysts (Mn@Bi2Se3@RGE-Exos) for efficient GBM therapy via improving the BBB penetration and enzyme-like catalytic activities. Interestingly, a photothermally activatable multiple enzyme-like reactivity is observed in such a nanosystem. Upon NIR-II light irradiation, Mn@Bi2Se3@RGE-Exos are capable of converting hydrogen peroxide into hydroxyl radicals, oxygen, and superoxide radicals, providing a peroxidase (POD), oxidase (OXD), and catalase (CAT)-like nanocatalytic cascade. This consequently leads to strong oxidative stresses to damage GBM cells. In vitro, in vivo, and proteomic analysis further reveal the potential of Mn@Bi2Se3@RGE-Exos for the disruption of cellular homeostasis, enhancement of immunological response, and the induction of cancer cell ferroptosis, showcasing a great promise in anticancer efficacy against GBM with a favorable biosafety profile. Overall, the success of this study provides a feasible strategy for future design and clinical study of stimuli-responsive nanocatalytic medicine, especially in the context of challenging brain cancers like GBM.

Energy-storing DNA-based hydrogel remodels tumor microenvironments for laser-free photodynamic immunotherapy

Photodynamic therapy (PDT) is a promising modality for cancer treatment. However, limited tissue penetration of external radiation and complicated tumor microenvironments (TMEs) restrict the antitumor efficiency of PDT. Herein, we report an energy-storing DNA-based hydrogel, which enables tumor-selective PDT without external radiation and regulates TMEs to achieve boosted PDT-mediated tumor immunotherapy. The system is constructed with two ultralong single-stranded DNA chains, which programmed partial complementary sequences and repeated G-quadruplex forming AS1411 aptamer for photosensitizer loading via hydrophobic interactions and π-π stacking. Then, energy-storing persistent luminescent nanoparticles are incorporated to sensitize PDT selectively at tumor site without external irradiation, generating tumor antigen to agitate antitumor immune response. The system catalytically generates O2 to alleviate hypoxia and releases inhibitors to reverse the IDO-related immunosuppression, synergistically remodeling the TMEs. In the mouse model of breast cancer, this hydrogel shows a remarkable tumor suppression rate of 78.3 %. Our study represents a new paradigm of photodynamic immunotherapy against cancer by combining laser-free fashion and TMEs remodeling.