Nongenetic Precise Neuromodulation and Spatiotemporal Neuroprotection for Epilepsy Therapy via Rationally Designed Multifunctional Nanotransducer.

The precise modulation of electrical activity in specific neuronal populations is paramount for rectifying abnormal neurological functions and is a critical element in the therapeutic arsenal for neurological disorders. However, achieving a balance between minimal invasiveness and robust neuroprotection poses a considerable challenge. Herein, we present a nanoneuromodulation strategy integrating neuroprotective features to effectively address epilepsy with minimal invasiveness and enable wireless functionality. Strategically engineered nanotransducer, adorned with platinum (Pt) decoration with titanium disulfide (TiS2) (TiS2/Pt), enables precise modulation of neuronal electrical activity in vitro and in vivo, ensuring exceptional temporal fidelity under millisecond-precision near-infrared (NIR) light pulses irradiation. Concurrently, TiS2/Pt showcase a pronounced enhancement in enzyme-mimicking activity, offering a robust defense against oxidative neurological injury in vitro. Nanotransducer-enabled wireless neuromodulation with biocatalytic neuroprotective capacity is highly effective in alleviating epileptic high-frequency neural activity and diminishing oxidative stress levels, thereby restoring redox equilibrium. This integrated therapeutic approach reduces the severity of epilepsy, demonstrating minimal invasiveness and obviating the requirements for genetic manipulation and optical fiber implantation, while providing an alternative avenue for neurological disorder treatment.

Robust, stretchable bioelectronic interfaces for cardiac pacing enabled by interfacial transfer of laser-induced graphene via water-response, nonswellable PVA gels.

Implantable cardiac pacemakers are crucial therapeutic tools for managing various cardiac conditions. For effective pacing, electrodes should exhibit flexibility, deformability, biocompatibility, and high conductivity/capacitance. Laser-induced graphene (LIG) shows promise due to its exceptional electrical and electrochemical properties. However, the fragility of LIG and the non-stretchability of polyimide substrates pose challenges when interfacing with the beating heart. Here, we present a simple method for fabricating robust, flexible, and stretchable bioelectronic interfaces by transferring LIG via water-responsive, nonswellable polyvinyl alcohol (PVA) gels. PVA solution penetrates the porous structure of LIG and solidifies into PVA xerogel as the solvent evaporates. The robust PVA xerogel enables the smooth transfer of LIG and prevents stretching of the LIG network during this process, which helps maintain its conductivity. When hydrated, the xerogel becomes a stable, nonswellable hydrogel. This gives the LIG-PVA hydrogel (LIG-PVA-H) composites with excellent conductivity (119.7 ± 4.3Ω sq-1), high stretchability (up to 420%), reliability (cyclic stretch under 15% strain, with ∼ 1-time resistance increase), and good stability in phosphate buffered saline. The LIG-PVA-H composites were used as biointerfaces for electrocardiogram signal recording and electrical pacing on rat hearts ex vivo and in vivo, using commercial setups and a custom-built implantable wireless device. This work expands the application of LIG in bioelectronic interfaces and facilitates the development of electrotherapy for cardiac diseases.

Injectable Mesh-Like Conductive Hydrogel Patch for Elimination of Atrial Fibrillation.

Irregular electrical impulses in atrium are the leading cause of atrial fibrillation (AF), resulting in fatal arrhythmia and sudden cardiac death. Traditional medication and physical therapies are widely used, but generally suffer problems in serious physical damage and high surgical risks. Flexible and soft implants have great potential to be a novel approach for heart diseases therapy. A conductive hydrogel-based mesh cardiac patch is developed for application in AF elimination. The designed mesh patch with rhombic-shaped structure exhibits excellent flexibility, surface conformability, and deformation compliance, making it fit well with heart surface and accommodate to the deformation during heart beating. Moreover, the mechanical elastic and shape-memory properties of the mesh patch enable a minimally invasive injection of the patch into living animals. The mesh patch is implanted on the atrium surface for one month, indicating good biocompatibility and stability. Furthermore, the conductive patch can effectively eliminate AF owing to the conductivity and high charge storage capability (CSC) of the hydrogel. The proposed scheme of cardiac bioelectric signal modulation using conductive hydrogel brings new possibility for the treatment of arrhythmia diseases.

Black Phosphorus Flake-Enabled Wireless Neuromodulation for Epilepsy Treatment.

Epilepsy is a prevalent and severe neurological disorder and generally requires prolonged electrode implantation and tether brain stimulation in refractory cases. However, implants may cause potential chronic immune inflammation and permanent tissue damage due to material property mismatches with soft brain tissue. Here, we demonstrated a nanomaterial-enabled near-infrared (NIR) neuromodulation approach to provide nongenetic and nonimplantable therapeutic benefits in epilepsy mouse models. Our study showed that crystal-exfoliated photothermal black phosphorus (BP) flakes could enhance neural activity by altering the membrane capacitive currents in hippocampus neurons through NIR photothermal neuromodulation. Optical stimulation facilitated by BP flakes in hippocampal slices evoked action potentials with a high spatiotemporal resolution. Furthermore, BP flake-enabled NIR neuromodulation of hippocampus neural circuits can suppress epileptic signals in epilepsy model mice with minimal invasiveness and high biocompatibility. Consequently, nanomaterial-enabled NIR neuromodulation may open up opportunities for nonimplantable optical therapy of epilepsy in nontransgenic organisms.

An oligomeric semiconducting nanozyme with ultrafast electron transfers alleviates acute brain injury.

Artificial enzymes have attracted wide interest in disease diagnosis and biotechnology due to high stability, easy synthesis, and cost effectiveness. Unfortunately, their catalytic rate is limited to surface electron transfer, affecting the catalytic and biological activity. Here, we report an oligomeric nanozyme (O-NZ) with ultrafast electron transfer, achieving ultrahigh catalytic activity. O-NZ shows electron transfer of 1.8 nanoseconds in internal cores and 1.2 picoseconds between core and ligand molecule, leading to ultrahigh superoxidase dismutase­like and glutathione peroxidase­like activity (comparable with natural enzyme, Michaelis constant = 0.87 millimolars). Excitingly, O-NZ can improve the 1-month survival rate of mice with acute brain trauma from 50 to 90% and promote the recovery of long-term neurocognition. Biochemical experiments show that O-NZ can decrease harmful peroxide and superoxide via in vivo catalytic chain reaction and reduce acute neuroinflammation via nuclear factor erythroid-2 related factor 2­mediated up-regulation of heme oxygenase-1 expression.

Catalytically active gold clusters with atomic precision for noninvasive early intervention of neurotrauma.

BACKGROUND: Neurotrauma is a worldwide public health problem which can be divided into primary and secondary damge. The primary damge is caused by external forces and triggers the overproduction of peroxides and superoxides, leading to long-lasting secondary damage including oxidative stress, wound infection and immunological reactions. The emerging catalysts have shown great potential in the treatment of brain injury and neurogenic inflammation, but are limited to biosafety issues and delivery efficiency. RESULTS: Herein, we proposed the noninvasive delivery route to brain trauma by employing highly active gold clusters with enzyme-like activity to achieve the early intervention. The decomposition rate to H2O2 of the ultrasmall gold clusters is 10 times that of glassy carbon (GC) electrodes, indicating excellent catalytic activity. The gold clusters can relieve the oxidative stress and decrease the excessive O2·- and H2O2 both in vitro and in vivo. Besides, gold clusters can accelerate the wound healing of brain trauma and alleviate inflammation via inhibiting the activation of astrocytes and microglia through noninvasive adminstration. decrease the peroxide and superoxide of brain tissue. CONCLUSIONS: Present work shows noninvasive treatment is a promising route for early intervention of brain trauma.

Carbon dot targeting to nitrogen signaling molecules for inhibiting neuronal death.

Free radical-induced oxidative damage and nitrosative stress have been identified as key factors in neuroinflammation responses after traumatic brain injury (TBI), with which reactive oxygen and nitrogen species (RONS), especially nitrogen signaling molecules, are strongly associated. Here, we prepared ultrasmall carbon dot (CD) by using a simple and facile method. In vitro assessment experiments show that the antioxidative CD exhibits an ultrahigh target-scavenging effect for nitrogen signaling molecules, especially the highly reactive ˙NO and ONOO-. However, CD can only partially eliminate conventional oxygen radials such as O2˙- and ˙OH, indicating CD has a preference for RNS modulation. Moreover, in vitro cell experiments and in vivo mice experiments reveal that CD can reduce the reactive oxygen species (ROS) level and lipid peroxidation, enhance superoxide dismutase (SOD) activity and GSSG level, and further improve the survival rate of neuron cells and TBI mice. These results declare that antioxidative CD could serve as an effective therapeutic for TBI.

Dual pH-triggered catalytic selective Mn clusters for cancer radiosensitization and radioprotection.

Hypoxia is known to be a common feature within many types of solid tumors, which is closely related to the limited efficacy of radiotherapy. Meanwhile, due to the non-discriminatory killing effect of both normal and cancer cells during the radiation process, traditional radiosensitizers could bring severe non-negligible side-effects to the whole body. In this work, stable and atomically precise Mn clusters which possess efficient pH-triggered catalytic selective capacity are developed rationally. Mn clusters could efficiently catalyze oxygen production in an acidic tumor microenvironment, while exhibiting strong reducibility and free radical scavenging ability in neutral circumstances. In vivo experiments show that Mn clusters are able to enhance the radiotherapy effect in the mouse model of 4T1 tumors and protect normal tissues from radiation at the same time. Thus, the present work provides a novel dual-functional strategy to enhance radiotherapy-induced tumor treatment by improving tumor oxygenation and protect normal tissues from radiation simultaneously.

Carbogenic Nanozyme with Ultrahigh Reactive Nitrogen Species Selectivity for Traumatic Brain Injury.

Reactive oxygen and nitrogen species (RONS), especially reactive nitrogen species (RNS) are intermediate products during incidence of nervous system diseases, showing continuous damage for traumatic brain injury (TBI). Here, we developed a carbogenic nanozyme, which shows an antioxidant activity 12 times higher than ascorbic acid (AA) and behaves as multienzyme mimetics. Importantly, the nanozyme exhibits an ultrahigh scavenging efficiency (∼16 times higher than AA) toward highly active RNS, such as •NO and ONOO- as well as traditional reactive oxygen species (ROS) including O2•-, H2O2, and •OH. In vitro experiments show that neuron cells injured by H2O2 or lipopolysaccharide can be significantly recovered after carbogenic nanozyme treatment via scavenging all kinds of RONS. Moreover, the carbogenic nanozyme can serve as various enzyme mimetics and eliminate the harmful peroxide and glutathione disulfide from injured mice, demonstrating its potential as a therapeutic for acute TBI.