Weekly Advanced Technologies〔69〕丨A Novel Acceleration Scheme for Ions丨T-Linker: What Changes Does It Bring to the R&D of Bio-orthogonal Chemical Drugs?

The compact laser accelerator is a type of advanced apparatus that utilizes lasers to accelerate particles. It is relatively more compact and energy-saving than traditional accelerators. However, the present technology of laser-accelerated ions has not yet reached the energy level of conventional accelerators. Recently, GONG Zheng and other researchers from the Institute of Theoretical Physics, Chinese Academy of Sciences, has proposed a new type of ion acceleration scheme, whose energy level is at least one order of magnitude greater than the current energy record of laser ion accelerators.

Bio-orthogonal chemistry refers to chemical reactions that can occur within living systems without affecting their own biochemical processes. In the resent past, a collaborative research has been launched by the research groups of CHEN Peng and XI Jianzhong from Peking University, KANG Xiaozheng from the Cancer Hospital of the Chinese Academy of Medical Sciences, LI Yan from Nanjing University, and LIN Jian from the Peking University Third Hospital. They have developed a bioorthogonal chimeric platform. By using the T-Linker, three drug molecules were integrated in a modular and site-specific manner to form a Multi-TAC for the simultaneous recruitment of multiple different types of immunity.

Based on the weekly diary of technology provided by the daily list of the NCSTI online service platform, we launch the column "Weekly Advanced Technologies" at the hotlist of sci-tech innovation. Today, let's check out No.69.

1. Physical Review Letters丨A Novel Acceleration Scheme for Ions

Schematic diagram of a scheme for slow laser-ion acceleration

A particle accelerator is a device that employs electromagnetic fields to accelerate charged particles and endow them with high energy. Owing to the limitation of radio frequency breakdown, the acceleration gradient of traditional accelerators can only reach up to 100 MeV/m. Compact laser accelerators, on the other hand, can theoretically achieve an acceleration gradient that is three orders of magnitude higher (>100 GeV/m) by utilizing plasma waves as the acceleration medium. This holds the promise of replacing traditional large-scale accelerators and demonstrating significant application value in such fields as particle and nuclear physics, laboratory astrophysical simulations, high-energy density science, and medical diagnosis and treatment.

Nevertheless, the current technology for laser-accelerated ions has not yet attained the energy level of traditional accelerators. The main challenge lies in the fact that ions possess large inertia and move relatively slowly, making it difficult for them to keep pace with the laser-accelerated structures that propagate at the speed of light.

Recently, GONG Zheng and other researchers from the Institute of Theoretical Physics, Chinese Academy of Sciences jointly proposed a novel ion acceleration scheme. This scheme utilizes the spatiotemporally coupled light pulse technology with adjustable velocity. By controlling the propagation velocity of the laser envelope to match the moving velocity of ions, synchronous, continuous and highly efficient acceleration of ions can be achieved.

Theoretical investigations have demonstrated that by employing a light field featuring a laterally shifting focus, ions can be accelerated to an energy level of GeV per nucleon within a gas plasma. This energy level is at least one order of magnitude greater than the current energy record of laser ion accelerators, which stands at ∼100 MeV/nucleon.

Furthermore, through Hamiltonian dynamics analysis, they analytically deduced the threshold conditions necessary for the successful capture and acceleration of ions. Additionally, they verified the universality and robustness of this proposed scheme via multi-dimensional plasma kinetic simulations.

This study has not only provided an effective solution to the critical problem of low energy in laser-ion acceleration, but also presented a novel perspective on leveraging spatio-temporally coupled optical pulses to address plasma physics challenges.

2. Cell丨T-Linker: What Changes Does It Bring to the R&D of Bio-orthogonal Chemical Drugs?

Bio-orthogonal chimeras recruit multiple immune cells to target 

the immune micro-environment of solid tumours 

Bio-orthogonal chemistry refers to chemical reactions that can occur within living systems without affecting their own biochemical processes. It can be said that bio-orthogonal chemistry plays an important role in the labelling, tracing and dynamic intervention of bio-molecules. In clinical drug development, bio-orthogonal chemistry is also widely used in drug development, delivery and mechanism of action studies. However, in the field of tumour immunotherapy, bio-orthogonal chemistry has not yet been fully applied.

In the resent past, a collaborative research has been launched by the research groups of CHEN Peng and XI Jianzhong from Peking University, KANG Xiaozheng from the Cancer Hospital of the Chinese Academy of Medical Sciences, LI Yan from Nanjing University, and LIN Jian from the Peking University Third Hospital. They have developed a bioorthogonal chimeric platform. By using the T-Linker, three drug molecules were integrated in a modular and site-specific manner to form a Multi-TAC for the simultaneous recruitment of multiple different types of immunity.

T-Linker can prepare Multi-TACs of different types, sizes and properties in a modular, programmed and standardized manner through three "mutually orthogonal" chemical reactions. This platform can also control the coupling ratio of drug molecules and achieve the in situ release of drugs through cleavable linkers, thus enabling flexible application in various scenarios.

Through this work, bioorthogonal reactions has ushered into the new era of 'combinatorial chemistry'. The application of bioorthogonal chemistry in drug coupling has been developed, and the in-depth cross-fertilization between chemical biology and tumour immunology has been significantly promoted.

3. Genome Research丨Researchers Develop DigNet, Demonstrating Intelligence in Gene Regulatory Networks

Flowchart of DigNet framework

Recently, the team led by LIU Zhiping Liu, affiliated with the School of Control Science and Engineering at Shandong University, has developed a novel pre-trained computational framework named DigNet. This framework combines discrete diffusion generation models and graph embedding methods, thereby achieving a new mode of end-to-end direct generation from single-cell RNA sequencing data to gene regulatory networks. Significantly, it not only enhances the accuracy and efficiency of gene regulatory network inference tasks but also provides a potent new tool for dissecting complex biomolecular networks, uncovering signalling pathways, and searching for disease biomarkers.

Gene regulatory networks accurately encode the intricate interactions between gene roles and functions within a cell, thus determining cell specificity. Despite decades of dedicated research efforts, the reverse engineering of gene regulatory networks from gene expression data still encounters substantial challenges, particularly in the construction of gene regulatory networks that precisely align with the specificity of cells and genetic backgrounds.

To this end, DigNet decomposes the network inference task into a series of multi-step diffusion processes with Markovian properties. Each step has applied a specific model to reconstruct a portion of the gene regulatory architecture, ensuring a high degree of fit between the network structure and the gene expression profile. This generative model has not only considered the complex regulatory relationships among multiple genes but also focused on the global structural information in the regulatory network. In addition, by combining the meta-cell integration technique with non-Euclidean discrete space modelling, DigNet has been able to effectively deal with the noise problem in the data and overcome the challenge of network sparsity.

4. Advanced Materials丨Hydrogel Adhesives: Building a Robust "Bond" to Guard Life

Hydrogel-based biotissue adhesives have received widespread attention in the fields of tissue sealing, wound repair, human-machine interfaces and implantable bioelectronic devices due to their excellent bio-compatibility and tunable physicochemical properties. However, the presence of a hydration layer on the surface of biological tissues and the disruption of inter- or intra-molecular interactions of polymers by water molecules usually result in the failure of hydrogel interfaces or matrix functionality, which diminishes their wet adhesive properties. Therefore, there is an urgent need to develop hydrogel-based bio-tissue adhesives with sufficient wet bonding capacity and swelling resistance to meet the demands of clinical applications.

Recently, the team led by Chen Yilong from Xi'an Jiaotong University proposed a novel strategy to improve the interfacial wet tissue adhesion of hydrogel adhesives and the swelling resistance of the matrix by coordinating the regulation of molecular structure and intermolecular interactions.

They took advantage of the unique structure of the hydrophobic amino acid derivative N-acryloylphenylalanine (APA), in which the carboxyl group and the phenyl ring are in the same structural unit. By combining multiple intermolecular hydrogen bonds and the electrostatic interactions mediated by zwitterionic groups, they developed a new type of hydrogel adhesive (PAAS). This adhesive can rapidly (~20 s) establish a firm adhesive interface on wet biological tissues (with an adhesive strength of 85 kPa, an interfacial toughness of 450 Jm⁻², and a burst pressure of 514 mmHg). Moreover, it can maintain the stability of its function and structure in a high-humidity environment (with a swelling rate of less than 4% within 10 days).

The results of systematic analyses showed that PAAS hydrogels could form strong adhesive interfaces with a wide range of organ tissues (liver, lung, heart, stomach, arteries and skin). In addition, by combining with thermoplastic polyurethane to assemble a ready-to-use bio-patch with asymmetric adhesive properties, PAAS patches demonstrated significant bio-tissue adhesion in several in vivo organ injury models in rats, rabbits, and swine, and could be used for emergency hemostasis and accelerated healing of organ injuries in vivo and to avoid the occurrence of postoperative tissue or organ adhesions.

In addition, PAAS hydrogels can maintain stable tissue adhesion with dynamic biological tissues in high humidity or underwater environments, which not only provides accurate and long-lasting physiological signal outputs for human health monitoring (pulse, ECG, and EMG), but also allows us to validate the wound sealing effect of PAAS patches in rabbit and porcine carotid artery injury haemorrhage models. 

The above design strategies and findings have not only offered valuable inspiration for the design of biotissue adhesives possessing potent wet bonding and anti-swelling properties but also presented new alternatives for the clinical treatment of emergency bleeding, tissue or organ damage, as well as hydrogel biointerfaces.

5. Neuroelectronics丨High-efficiency Neural Regulation Chips Keep Brain-Machine Interface Technology on Track

The eight-channel neurostimulation chip device, which mainly consists of a waveform generator, a charge balancer, and a high-voltage driver, was tested and validated in electrode models, PBS solutions, and animal experiments.

With the rapid advancement of neuroscience and brain-computer interface technology, the achievement of efficient and safe neurostimulation in neuromodulation has emerged as a crucial focus in both scientific research and medical arenas.

Recently, an eight-channel high-voltage neurostimulation integrated circuit (IC) has been jointly designed by researchers from Tianjin University, Beijing Institute of Technology, Tianjin University of Traditional Chinese Medicine, and Southern University of Science and Technology. This circuit employs biphasic exponential waveform output and charge balance, thereby enhancing the efficiency and safety of neurostimulation and opening up new avenues for the further development of neuromodulation and implantable devices.

A significant highlight lies in the improvement of power efficiency. By adopting an exponential waveform output in lieu of the traditional constant-current stimulation mode, the power efficiency has been increased to an impressive 98%. This has not only reduced power consumption but also effectively curtailed the heat emission of the device during its operation.

This chip has been verified through both in vitro and in vivo experiments. During the in vitro tests, a wide range of simulation experiments were carried out using different electrode-tissue interface models. As a result, nerve stimulation with minimal residual charge was successfully accomplished. In the in vivo experiments, by stimulating the vagus and sciatic nerves in rats, notable muscle contraction effects were witnessed. This clearly demonstrates the chip's great potential for practical applications.

The research results have not only provided an important tool for neuroscience research but are also expected to open a new chapter in the field of intelligent medical devices. In this way, neuro modulation technology can better serve clinical and rehabilitation therapy.

Columnist: Li Xiaoxiao

Translator: Liu Kaiyuan