This issue of Biomedical Information focuses on ten cutting-edge breakthroughs, covering key areas such as cancer immunotherapy, neurodevelopmental mechanisms, and regenerative medicine. Highlights include: unlocking new anti-cancer potential of CAR-T with liver metabolite BHB; Sun Yat sen University team reveals new immune escape loop in esophageal cancer; Extracellular vesicles from brain organoids bring hope for refractory depression; The first invasive brain computer interface medical device and implantable ocular stimulator have both been approved for market launch. These achievements, from basic research to clinical translation, provide new ideas and technological paths for disease diagnosis and treatment.

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1、 BHB, a natural product of the liver: the metabolic key to unlocking the anti-cancer potential of CAR-T cells

Recently, a study published in the journal Cell revealed the key role of β – hydroxybutyric acid (BHB), a natural metabolic byproduct of the liver, in enhancing the anti-cancer efficacy of CAR-T cell therapy. This discovery provides a novel and efficient metabolic intervention strategy for enhancing adoptive cellular immunotherapy.
The research team first explored dietary regulation and found that mice fed a ketogenic diet had significantly increased levels of BHB in their bodies, accompanied by improved tumor control ability. This suggests that BHB may be associated with anti-tumor immune activity. However, considering the difficulty and uncertainty of maintaining a ketogenic diet for cancer patients in the long term, researchers have turned to a more direct intervention approach: supplementing BHB alone. In various preclinical cancer models, direct supplementation of BHB successfully replicated the benefits of ketogenic diet, significantly improving the expansion ability, persistence, and tumor killing activity of CAR-T cells in vivo.
At the mechanistic level, in-depth research has found that BHB can be effectively taken up and integrated into the core metabolic pathway – the tricarboxylic acid cycle – by CAR-T cells, thereby efficiently producing more energy (ATP) to meet their rapidly increasing energy demands for activation, amplification, and execution of killing functions. Further genetic analysis showed that CAR-T cells treated with BHB expressed more genes related to T cell activation, effector function, and memory formation. It is crucial that when researchers knocked out the key enzyme responsible for converting BHB into usable energy in CAR-T cells, all the enhancing effects of BHB disappeared, confirming that its benefits are entirely dependent on the metabolic utilization of BHB by cells.
This study not only elucidates the specific mechanism by which BHB enhances CAR-T cell function through metabolic reprogramming, but also highlights the enormous potential of simple metabolic interventions in cancer immunotherapy. Based on this, relevant clinical trials have been launched to verify whether BHB supplementation can safely and effectively enhance the clinical efficacy of CAR-T therapy in cancer patients, which is expected to bring new breakthroughs to the current tumor immunotherapy landscape.

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2、 Sun Yat sen University team reveals mechanism of NFIB inhibiting iron death resistance therapy

Professor Jiang Guanmin’s team at Sun Yat sen University has made significant progress in the research of drug resistance in castration resistant prostate cancer (CRPC) treatment. This study reveals for the first time that nuclear factor I/B (NFIB) is a key molecule in CRPC’s resistance to ferroptosis, and drives drug resistance through a novel “phase separation” transcriptional regulatory mechanism, providing a new combination therapy strategy for overcoming the challenges of CRPC treatment.
CRPC faces severe challenges in clinical treatment due to its susceptibility to traditional therapies and unclear mechanism of iron death regulation. The team found that NFIB was significantly upregulated in CRPC tissues and cell lines, and its expression level was positively correlated with the key regulatory protein SLC3A2 of ferroptosis, suggesting that NFIB may be involved in inhibiting ferroptosis. Functional experiments have confirmed that knocking down or knocking out NFIB can significantly enhance the sensitivity of CRPC cells to ferroptosis, confirming that NFIB is a key inhibitor of ferroptosis.

The core breakthrough of the research lies in elucidating the unique mechanism by which NFIB functions. NFIB does not form “biological molecular aggregates” (nuclear aggregates) in the nucleus through traditional pathways, but rather through the intrinsic disordered regions of its protein N-terminus and C-terminus. This phase separation process relies on the deacetylation modification of NFIB by the deacetylase SIRT7, thereby dynamically regulating the formation and function of aggregates. In this condensate, NFIB directly binds to and activates the transcription of SLC3A2, thereby enhancing the cell’s antioxidant defense ability and ultimately leading to resistance to ferroptosis.

The translational value of the research has been validated in in vivo experiments. The combined use of NFIB pathway intervention and iron death inducers can significantly inhibit the growth of CRPC xenografts, with better efficacy than monotherapy. This indicates that targeting the NFIB mediated phase separation transcription mechanism, combined with inducing ferroptosis, has the potential to become a highly promising new therapeutic approach for CRPC. In summary, this study not only establishes NFIB as the core hub of iron death resistance in CRPC, but also innovatively reveals its gene regulation mode based on phase separation, laying a solid theoretical foundation for the development of precise combination therapies for CRPC.

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3、 Shandong University team uses in vivo CAR technology to provide a new framework for the treatment of autoimmune diseases

The team led by Jing Weiqiang, Jiang Xinyi, and Li Tao from Shandong University has published a groundbreaking study in the top journal Cell Stem Cell, opening up a new path for the treatment of autoimmune diseases. This study focuses on autoimmune hepatitis (AIH) with limited clinical treatment progress, and one of its core pathogenic mechanisms is the overactivation and dysfunction of follicular helper T (Tfh) cells.

Faced with the challenge of traditional therapies being difficult to precisely regulate specific immune cells, the team innovatively developed the “in vivo CAR Tfh cell” technology. Researchers have designed an amino acid derived lipid nanoparticle (LNP) as a delivery carrier to directly and efficiently introduce self amplifying RNA encoding transcription factors Foxp3 and CYP2D6 (AIH key self antigen) specific CAR into Tfh cells in vivo. This ingenious design achieves dual reprogramming: on the one hand, Foxp3 endows Tfh cells with key regulatory features; On the other hand, the CAR structure enables it to specifically recognize and target diseased liver cells expressing CYP2D6.

The engineered CAR Tfh cells exhibit excellent therapeutic properties: they can preferentially homing to the liver, and after antigen dependent aggregation at the target site, not only transform into regulatory phenotypes, but also actively inhibit peripheral pathogenic T and B cell responses, thereby locally rebuilding immune tolerance. In the AIH-II mouse model, this strategy significantly reduced liver tissue damage and restored liver immune homeostasis.

The significance of this study lies in its establishment of a modular universal method for in situ T cell reprogramming in vivo. By replacing the targeted antigen of CAR, the platform is expected to expand to other autoimmune diseases driven by specific immune cell subpopulations, providing a strong conceptual framework and technological foundation for the development of a new generation of precise and efficient immunotherapy.

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4、 Precise targeting of NLRP3 by brain organoid extracellular vesicles brings new hope to refractory depression

Depression is a major global mental health issue affecting over 350 million people, with a significant portion of patients experiencing poor response to existing medications, making it a difficult to treat depression. Recent studies have revealed the core role of neuroinflammation in its pathological mechanism, providing key targets for the development of novel therapies.

Extracellular vesicles are nanoscale vesicles secreted by cells, capable of carrying various bioactive substances such as proteins, lipids, and nucleic acids, and serving as key mediators of intercellular communication. Its unique advantage lies in its ability to cross the blood-brain barrier and deliver therapeutic substances precisely to the brain. At present, cutting-edge research mainly focuses on two strategies: one is to use natural exosomes derived from stem cells or brain organs, and the other is to construct engineered exosomes with targeted functions through genetic engineering.

A recent study published in iScience demonstrated the potential of the first strategy. The research team isolated extracellular vesicles (OExo) from brain organoids cultured with human induced pluripotent stem cells. These OExo are rich in neurotrophic factors and immune regulatory proteins. In cell and animal experiments, OExo has been shown to accurately inhibit the key neuroinflammatory signaling pathway NLRP3 inflammasome Aspase-1-IL-1 β, effectively reverse inflammatory pathological states, repair neuronal damage, and significantly improve behavioral symptoms in depression model mice, demonstrating good safety. These studies not only deepen our understanding of the neurobiological mechanisms of depression, but also highlight the broad prospects of the next generation of treatment models moving from “symptomatic relief” to “precise repair”.

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5、 PNAS: Xiong Zhiqi and his team reveal CDKL5 driven dendritic spine structure remodeling mechanism

On February 18th, Xiong Zhiqi and his team published an important study in the Proceedings of the National Academy of Sciences (PNAS), which thoroughly elucidated the core role of cyclin dependent kinase like 5 (CDKL5) in regulating excitatory synaptic structure and function, and revealed the key molecular pathological mechanism of CDKL5 deficiency (CDD) caused by its mutations.

This study is the first to discover that CDKL5 protein can undergo liquid-liquid phase separation (LLPS) under physiological conditions and form dynamic co aggregates with the postsynaptic scaffold protein PSD95. This type of biomolecule aggregate serves as the “tissue center” and efficiently drives the spatial rearrangement of components in the postsynaptic dense zone (PSD), directly promoting the enlargement and structural maturity of dendritic spines, which is the structural basis of synaptic plasticity.

Further research has confirmed that pathogenic mutations related to CDD specifically impair the LLPS ability of CDKL5, leading to obstruction of its co aggregation with PSD95 and disrupting the normal assembly of postsynaptic signaling complexes. This provides a direct mechanism explanation for the synaptic developmental abnormalities in CDD from the perspective of phase separation.

In addition, the team successfully identified the Rho guanylate exchange factor Kalirin7 as a key downstream effector molecule of CDKL5. CDKL5 regulates the local enrichment and activity of Kalirin7 through phase separation condensation, thereby precisely coordinating the remodeling dynamics of actin cytoskeleton in dendritic spines, directly coupling signal transmission with structural changes. This study not only established the core regulatory role of CDKL5 in synaptic structural plasticity, but more importantly, for the first time established liquid-liquid phase separation as the fundamental biophysical mechanism for CDKL5 to coordinate synaptic molecular events and restructure PSD nanostructures. This opens up a new perspective for a deeper understanding of the synaptic pathological mechanisms underlying neurodevelopmental disorders such as CDD, and provides potential therapeutic targets for intervention strategies targeting phase separation processes.

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6、 Prussian blue nanoparticles have been published in a Nature journal, opening up a new path for the treatment of myocardial ischemia-reperfusion injury

Recently, a study published in a sub journal of Nature has opened up a new path for the treatment of myocardial ischemia-reperfusion injury (MIRI). The research team from Shanghai Jiao Tong University School of Medicine has confirmed for the first time that MIRI is a disease driven by “composite” cell death (PANoptosis) by analyzing the heart tissue of patients with acute myocardial infarction. In the face of this complex pathological process involving the interaction of multiple cell death pathways, traditional single target therapy strategies have limited effectiveness.

The research team innovatively transformed Prussian blue, an antidote with a hundred years of clinical application history, into nanoparticles (PB NPs) and constructed a targeted delivery system by encapsulating them with platelet membrane PB@PM Molecular dynamics simulations have confirmed that the nanoparticles can strongly bind to the core components of PANoptosis. In the MIRI mouse model, PB@PM Exhibited excellent cardiac targeting ability, effectively improved cardiac function and significantly reduced myocardial infarction area by simultaneously blocking multiple key links of PANoptosis and correcting immune inflammatory imbalances.

The breakthrough significance of this study lies in breaking away from the traditional approach of targeting a single pathway and utilizing ancient drugs that have been engineered to achieve multi-target synergistic intervention on the core mechanism of MIRI – PANoptosis. This not only provides a new concept validation and highly promising candidate strategy for developing efficient and precise cardiovascular disease therapies, but also marks a crucial step in the deep integration of nanotechnology and pathological mechanisms to solve complex disease treatment challenges.

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7、 New sequencing technology reveals’ hidden genes’ of autism

Autism Spectrum Disorder (ASD) affects approximately 1% of children worldwide, and its complex genetic basis has always been a mystery that the scientific community urgently needs to solve. Recently, scientists from the University of California, San Diego and other institutions published a groundbreaking study in Cell Genomics. They used the “long read long whole genome sequencing” technology to conduct in-depth analysis on 267 individuals from 63 families with autism, successfully revealing “hidden” gene variations that traditional methods are difficult to capture, opening a new window for understanding the genetic roots of autism.

Compared to widely used short read sequencing, long read sequencing technology can span complex repetitive regions and structures in the genome, significantly improving the detection ability of key variants. Research data shows that this technology has increased the detection rates of destructive structural variations and tandem repeat sequences by 33% and 38%, respectively. In addition, the team has also discovered for the first time novel structural variations in a completely new exon region and identified complex mutation patterns such as nested replication deletion events. By integrating DNA methylation data, the study further revealed genetic events with significant biological impacts, such as deletion of imprinting gene regions.

The technological advantage directly translates into a deeper explanation of the heritability of diseases. Research has shown that these rare structural variations discovered can explain approximately 7.4% of the heritability of autism, and with the deepening of technological applications, this proportion is expected to significantly increase in the future. Long read sequencing can not only depict a more complete gene map, but also simultaneously obtain diverse functional information, providing a powerful tool for research from genetic variation to functional impact.

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8、 Xie Dan and his team from Sun Yat sen University reveal a new immune escape loop in esophageal cancer

Professor Xie Dan and his team from Sun Yat sen University have published an important study in the authoritative journal Advanced Science, which deeply reveals the underlying mechanism of limited efficacy of immunotherapy for esophageal squamous cell carcinoma (ESCC). This study focuses on a key molecule called NIPAL1, which systematically elucidates a novel loop driving the formation of an immunosuppressive tumor microenvironment.

Research has found that in ESCC, NIPAL1 does not rely on its classical magnesium ion transport function, but recruits non receptor tyrosine kinase HCK to promote phosphorylation of the key glycolytic enzyme LDHA. This effect significantly enhances the glycolytic flux and lactate production of tumor cells. Subsequently, the accumulated lactate acts as a precursor substance, promoting lactylation modification of histone H3 lysine 18, which is an emerging epigenetic regulatory marker. Abnormal H3K18 lactylation leads to transcriptional activation of NIPAL1 expression, forming a positive feedback loop of “NIPAL1-HCK/LDHA-lactate-H3K18la-NIPAL1”.

The continuous operation of this loop not only reshapes the metabolic state of the tumor, but more importantly, seriously damages the function of CD8 ⁺ T cells in the tumor microenvironment, thereby promoting immune escape. Research has confirmed at the intervention level that using inhibitors to block HCK or histone acetyltransferase p300 can effectively break this malignant loop, restore anti-tumor immune response, and make originally resistant tumors insensitive to anti-PD-1 immune checkpoint blockade therapy.

Clinical correlation analysis further supports its translational value: in patient samples, high expression of NIPAL1 and its loop related molecules is significantly correlated with poor immune therapy efficacy. This study not only reveals the core network driving the progression of ESCC and immune therapy resistance, but also provides new combination therapy targets for overcoming resistance, namely enhancing the efficacy of existing immune therapies by targeting HCK or epigenetic regulators, which has important clinical guidance significance.

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9、 The first invasive brain computer interface medical device has been approved for market launch

Recently, the National Medical Products Administration officially approved the registration application of Borui Kang Medical Technology (Shanghai) Co., Ltd.’s Implantable Brain Computer Interface Hand Movement Function Compensation System (NEO). As the world’s first approved invasive brain computer interface medical device, this product marks the official entry of this technology into the clinical application stage, and is a milestone event for China’s brain computer interface industry to shift from technical verification to commercial implementation.

The system consists of multiple core software and hardware components, including brain computer interface implants, implanted EEG electrode kits, EEG signal transceivers, pneumatic glove devices, and EEG coding software. It adopts minimally invasive implantation outside the dura mater and wireless power communication technology, collects neural signals from the cerebral motor cortex, decodes them, and drives pneumatic gloves to assist patients with limb paralysis caused by cervical spinal cord injury in restoring hand grasping function. Clinical trial data shows that three months after surgery, the subjects achieved a 100% response rate to the assisted grasping of the system, and their hand function scores significantly improved, verifying the safety and clinical effectiveness of this semi invasive technique pathway.

It is worth noting that the value of this product is not limited to functional compensation. After detaching from external support, the first subject not only improved their grip ability, but also independently wrote, showing positive signs of neural remodeling, indicating that this technology is expected to be upgraded from functional assistance to neurological rehabilitation therapy in the future. The currently approved NEO 1.0 version is mainly aimed at specific spinal cord injury patients, while the 2.0 version under development will expand to higher throughput and wider indications (such as fine motor and language decoding), with huge market potential.

This approval is due to strong support from national policies. Brain computer interfaces have been included as a key future industry to be cultivated in the 15th Five Year Plan. The National Medical Products Administration uses pre evaluation mechanisms such as “early intervention and research review linkage” to tilt resources and accelerate the launch of innovative products. At the same time, the industrial cultivation plan at the local level, such as Shanghai, has also clearly defined the goals for promoting subsequent products. With Borui Kang taking the lead in breaking through, the product development and clinical trial processes of many companies in the industry are expected to accelerate synchronously.

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10、 Implantable ocular muscle nerve stimulator approved for market launch

Recently, the National Medical Products Administration officially approved the registration of the “Implantable Eye Muscle and Nerve Stimulator” submitted by Chaomu Technology (Beijing) Co., Ltd. This product belongs to the third category of active implantable medical devices, and its approval marks a significant breakthrough for China in the field of ophthalmic nerve regulation therapy, which is a global first.

This product consists of an implanted stimulator and a specific external power supply device, which need to be used in combination. Its scope of application is clearly defined as the improvement of congenital horizontal nystagmus symptoms in patients aged 8 years and above. The core mechanism of the product lies in the application of innovative implantable extraocular muscle nerve muscle electrical stimulation technology, which directly acts on the extraocular rectus muscle through electrodes to intervene and improve the involuntary rhythmic swing of the eyeball. Compared to traditional therapies, this technological pathway has significant advantages such as minimal local trauma, strong controllability of stimulation parameters, and more stable expected treatment outcomes.

The research and development process of this product spans more than 20 years, led by Professor Wang Lejin’s team from the Ophthalmology Department of Peking University People’s Hospital to complete core technological innovation. Its pre-market clinical trials were conducted in several top ophthalmic centers in China, with a total of 71 patients enrolled. The results showed that it can effectively improve patients’ macular foveal fixation time, significantly improve tremor symptoms, and enhance visual quality, verifying its effectiveness and safety. It is worth noting that the product has successively entered the Special Review Procedure for Innovative Medical Devices of the National Medical Products Administration during the research and development process, and has obtained relevant recognition from the US Food and Drug Administration, reflecting its international level of innovation and the efficiency of China’s review and approval system in supporting cutting-edge technology.

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