BackgroundPhysical health is the basic indicator to evaluate the health of drug addicts after the process of drug rehabilitation. In order to better improve the deficiency degree of physical health of drug addicts, it is necessary to carry out a systematic review.ObjectiveTo explore the effects of exercise intervention on the physical health of individuals undergoing compulsory drug rehabilitation using Meta-Analysis, aiming to provide evidence-based support for improving their physical health.MethodsRandomized controlled trials (RCTs) published between 2019 and December 2024, examining the impact of exercise intervention on the physical health of compulsory detoxification individuals, were retrieved from databases including Web of Science, PubMed, Cochrane Library, Medline, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Chinese Journal Database. The quality of included studies was assessed using the Cochrane risk-of-bias assessment tool. RevMan 5.4 software was employed for heterogeneity testing, effect size synthesis (using mean difference [MD] and 95% confidence interval [CI]), and generation of forest plots, funnel plots, and quality assessment diagrams. Subgroup analyses were performed to evaluate sensitivity and heterogeneity of the included studies.ResultsExercise intervention effectively improved the physical health of compulsory drug rehabilitation individuals, particularly in physical fitness indicators: sit-and-reach test [MD = 3.92, 95%CI = (3.23, 4.62), P<0.001], single-leg standing with eyes closed [MD = 7.03, 95%CI = (6.05, 8.02), P<0.001], grip strength [MD = 1.23, 95%CI=(0.06, 2.39), P = 0.04], and choice reaction time [MD=-0.03, 95%CI=(-0.05, -0.01), P = 0.002]. Improvements in physical function were also observed; however, the increase in vital capacity [MD = 86.81, 95%CI=(-1.56, 175.17), P = 0.05] did not reach statistical significance.ConclusionThis meta-analysis provides evidence that exercise intervention significantly improves specific physical health deficits—namely flexibility (sit-and-reach), balance (single-leg stance), muscular strength (grip strength), cardiopulmonary function (vital capacity), and sensorimotor coordination (choice reaction time)—in individuals undergoing compulsory rehabilitation. It is recommended to adopt a combination of aerobic and traditional fitness exercises, with at least 3 sessions per week, each lasting no less than 40 minutes, and a duration of over 12 weeks, providing scientific evidence for drug rehabilitation practices. These indicators were selected because they directly reflect the multisystem damage (muscular, neural, and cardiorespiratory) caused by chronic substance use. However, this study acknowledges the limitation that psychological and neurocognitive outcomes (e.g., cravings, mood, executive function), which are crucial in addiction treatment, were not included in the eligibility criteria and systematic analysis. The follow-up research will combine physical and psychological indicators to conduct a comprehensive evaluation of the intervention effect of exercise on drug rehabilitation.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420251029820.
Tryptophan modulates the impact of prolactin on insomnia in perimenopausal women: a cross-sectional study
BackgroundInsomnia is highly prevalent among perimenopausal women and exerts detrimental effects on physical health, psychological well-being, and overall quality of life. However, its underlying mechanisms remain incompletely understood. This cross-sectional study aimed to identify factors associated with insomnia in perimenopausal women.MethodsA total of 187 perimenopausal women aged 45–55 years were enrolled. Insomnia, anxiety, and depression severity were assessed using the Insomnia Severity Index (ISI), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9), respectively. Serum levels of relevant amino acids and hormones were measured. Spearman correlation and linear regression analyses were performed to examine the associations among prolactin levels, tryptophan levels, insomnia, anxiety, and depression. Moderation analysis was further conducted to evaluate the potential moderating role of tryptophan in these relationships.ResultsSerum prolactin levels were positively associated with scores of ISI, GAD-7, and PHQ-9. Furthermore, prolactin levels were positively correlated with the severity of sleep-onset difficulties, sleep maintenance problems, noticeability of impairment, and sleep-related distress. Of note, serum tryptophan levels significantly moderated the association between prolactin levels and ISI scores (β = 0.227, 95% CI = 0.04–0.41, p = 0.0148). To wit, he positive relationship between prolactin levels and insomnia severity was stronger in perimenopausal women with higher serum tryptophan levels compared with those with lower levels.ConclusionsThe moderating effect of serum tryptophan on the relationship between prolactin levels and insomnia in perimenopausal women helps us understand the neuroendocrine mechanisms underlying perimenopausal insomnia and may inform future research on targeted preventive and therapeutic strategies.
Research trends and knowledge mapping of transcranial direct current stimulation in depression: a bibliometric study based on web of science, Scopus, and PubMed (2000-2025)
BackgroundDepressive disorders are clinically heterogeneous and mechanistically complex psychiatric conditions. Transcranial direct current stimulation (tDCS), a key non-invasive neuromodulation technique, has expanded rapidly in both therapeutic application and mechanistic research. However, the field is marked by rapid publication growth, thematic diversity, and variability in evidence quality. A systematic quantitative synthesis is therefore needed to map the research landscape, identify hotspots, and inform future directions.MethodsA systematic search was conducted for English-language publications in the Web of Science Core Collection (WoSCC), Scopus, and PubMed using the terms (“Transcranial direct current stimulation” OR “tDCS”) AND (“depression” OR “major depressive disorder” OR “depressive disorder” OR “MDD”). Only articles and reviews were included. Records from 2026 and non-research publications, including conference abstracts, editorials, letters, news items, and errata, were excluded. Deduplication was performed using DOI-based matching followed by title-assisted matching. Bibliometrix (R), VOSviewer, and CiteSpace were used to analyze publication trends, contributions by countries/regions, institutions, authors, and journals, collaboration networks, keyword co-occurrence, thematic clustering, and burst terms. Citation analysis was based on WoSCC data only.ResultsResearch on tDCS for depression showed sustained growth, with marked acceleration after 2020 and a peak in 2024. The United States, Germany, and Brazil occupied central positions in both productivity and international collaboration, with the United States ranking first in publication volume. Major research hubs included the Universidade de São Paulo, the University of Toronto, and Harvard University, while Brain Stimulation, Journal of Affective Disorders, and Frontiers in Psychiatry were the leading publication venues. Highly cited studies mainly focused on neurophysiological mechanisms, pivotal randomized controlled trials, and evidence-based guidelines. Keyword analyses indicated a shift from early attention to cortical excitability, safety, and short-term efficacy toward a more integrated framework involving prefrontal-targeted stimulation, cognitive function, functional connectivity, treatment outcomes, and cross-disorder applications.ConclusiontDCS research in depression is entering a multidimensional and interdisciplinary phase, with increasing emphasis on network-level mechanisms and precision intervention. Functional connectivity is emerging as a potential biomarker for patient stratification and outcome prediction. Further progress depends on multicenter standardization, reproducible analytic pipelines, and high-quality comparative effectiveness research.
Going Non-Viral: Gene Delivery Enters Its Translation Era
CEO, BreezeBio
Kunwoo Ryan Lee, PhD, knew as early as 2012 that solving the delivery problem would be crucial in fulfilling the promise of the newly discovered CRISPR-Cas9 gene editing technology. He felt strongly that gene editing had potential to transform medicine by curing genetic disorders, but the viral and non-viral vectors available at the time had significant drawbacks. With the support of CRISPR pioneers Jennifer Doudna and Stanley Qi, Lee completed his doctoral thesis on a gold nanoparticle delivery system for Cas9 ribonucleoprotein. He went on to co-found BreezeBio, formerly GenEdit, in 2016 with the aim of creating the next generation of gene editing-based therapeutics. To realize that goal, Lee and his team looked beyond traditional viral gene delivery systems and instead invented a new technology from the ground up.
Most clinical gene therapy trials use viral vectors, including retroviruses, lentiviruses, adenoviruses, and adeno-associated viruses. However, viral vectors are limited in the size of the gene they can deliver. They also tend to trigger strong immune reactions and usually can’t be dosed more than once due to acquired immunity.
Non-viral vectors are an alternative technology that offer greater gene loading capacity, more straightforward preparation, and less likelihood of triggering problematic immune reactions. BreezeBio and other biotechnology companies are reimagining gene delivery through non-viral approaches like targeted LNPs, transposons, and novel chemistry.
BreezeBio’s hydrophilic nanoparticle (HNP) platform, NanoGalaxy, hearkens back to Lee’s doctoral work. Lee said he and his cofounders realized that a hydrophobic molecule was needed to deliver a gene payload into cells, because the cell membrane is a lipid bilayer. Lee also noted that the best molecule for targeting different cell types is an antibody, a hydrophilic molecule. Pairing these two elements introduced a complex manufacturing challenge that the company solved by using a polyamide as a backbone structure and conjugating a hydrophobic small molecule to that backbone for targeting, resulting in the hydrophilic HNP. The company then used artificial intelligence to optimize HNPs for different tissue types.
“Using the platform, we have demonstrated that we can deliver to the spleen, immune system, heart, and lung,” Lee said. The firm also developed a set of nanoparticles targeted to the central nervous system.
Based on those targeted delivery profiles, the Brisbane, California-based BreezeBio has worked with multiple partners to provide delivery solutions for their products, including a multiyear collaboration with Genentech, a member of the Roche Group, signed in 2024. Meanwhile, the company is also advancing its own pipeline of therapeutics built on the NanoGalaxy platform, including a lead candidate for type 1 diabetes, as well as investigational therapies for autoimmune disease and cancer.
Lee said a key advantage of the NanoGalaxy platform for their pipeline, which heavily leans toward autoimmune disease, is that, unlike a viral vector, the company’s studies have shown it does not activate the innate immune system. “That enabled us to use our technology for autoimmune applications and in more targeted oncology applications, as well,” Lee said.
Snug as a bug in a rug
The red flour beetle, a notorious scourge of grain and cereal stores, is the surprising source of Bio-Techne’s transposon-based, non-viral gene delivery system. The system, dubbed TcBuster for the beetle’s scientific name, Tribolium castaneum, was invented by B-MoGen, a spin-out of the University of Minnesota, which was acquired in 2019 by Minneapolis-based Bio-Techne. Researchers at B-MoGen and Bio-Techne developed a hyperactive version of the natural TcBuster transposon by creating a library of three million unique genetic variants and screening each in mammalian cells. In a proof-of-concept study, CAR NK cells engineered using TcBuster demonstrated in vitro functionality and improved survival in a preclinical model of Burkitt lymphoma with a single dose.1
“The reason you want a hyperactive version is that wild-type transposon systems are fairly low activity,” said Miles Smith, PhD, a product manager for cell and gene therapy at Bio-Techne. “For generating a cell therapy, you want something that’s going to be comparable to the state of the field, and that’s lentivirus.”
Smith said the TcBuster system, which comprises an mRNA encoding transposase and a DNA transposon, can be produced faster than a lentiviral vector. The system is also more scalable, more cost-effective, and has increased gene cargo capacity, according to Smith. TcBuster can deliver multiple genes in a single vector, and it can be multiplexed with other gene therapy tools. “If you wanted to use base editors or CRISPR-based knockout gene editing in conjunction with TcBuster, you could do that in one step, compared to multiple steps with a viral system,” Smith said.
Unlike other commercial transposon systems for gene delivery, like Sleeping Beauty and PiggyBac, Smith said TcBuster is not restricted by exclusive licensing. “The turnaround time for GMP material is just a couple of months,” Smith said. “Versus something that might take a lot longer if you have to go through licensing or create a viral batch.”
Gene therapy SORTed
ReCode Therapeutics is developing a pipeline of genetic medicines based on its selective organ targeting (SORT) LNP platform, which adds an additional lipid to the standard LNP formulation, allowing it to zero in on specific organs. Conventional LNPs comprise four lipids—cholesterol, a helper phospholipid, a PEGylated lipid, and an ionizable lipid—that encapsulate a therapeutic gene cassette. These traditional LNPs are primarily taken up by the liver after intravenous administration, limiting their usefulness for other organs and systems. ReCode engineered its SORT LNPs with a biochemically distinct fifth lipid that enables the body to direct the particle to the targeted organ, such as the lung or spleen, bypassing the liver, if necessary.
“Because mRNA in a cell has a relatively short half-life, maybe a day or so, in order to have constant protein production, you need to administer it relatively frequently,” Vladimir Kharitonov, PhD, senior vice president of CMC and pharmaceutical sciences at ReCode, said. “With viral delivery, you can’t really administer it repeatedly.”
The Menlo Park, California-based firm’s two clinical-stage therapies are given by inhalation using a nebulizer. SORT lipids enable targeting specific cell types in the lung epithelium.
In 2024, ReCode presented preclinical data from its cystic fibrosis program showing its mRNA-based therapeutic RCT2100 significantly restored CFTR function in human bronchial epithelial cells derived from patients with cystic fibrosis. In vivo studies using a ferret model demonstrated improvement in mucociliary clearance. ReCode launched the first clinical trial of RCT2100 later that year. The LNP for RCT2100 contains SORT lipids to fine-tune its delivery to the airway epithelial cell types that have a defective or mutated CFTR protein, causing cystic fibrosis. The company is also developing a second mRNA therapy delivered via SORT LNP, RCT1100, for primary ciliary dyskinesia, which targets different cell types in the lung epithelium.
From idea to therapy faster
Gene delivery is just one of many services offered by GenScript to support research from discovery through clinical testing, including gene synthesis, CRISPR reagents, antibodies, and more.
Senior Director, GMP Manufacturing
GenScript
“Gene editing is entering a new era, and the focus has shifted from discovery to translation,” said Jianpeng Wang, PhD, senior director of nucleic acid and peptide R&D at GenScript. “Our goal at GenScript is to help scientists move from idea to therapy faster.”
When it comes to non-viral vectors, the firm offers off-the-shelf and bespoke solutions to fit the customer’s need for delivery of DNA, RNA, siRNA, peptides, and other molecules. Through its targeted LNP service, GenScript offers LNPs designed to enhance precision in directing genetic material to cells. GenScript’s ReadyEdit LNP solutions include Cas9 knock-in and knock-out, Cas12 knock-out, and base or prime editing tailored for the customer’s needs.
“In our ecosystem, we include all of the materials needed,” Wang said. “This integration can help scientists evaluate gene editing efficiency early, both ex vivo and in vivo.”
Wang said the choice of a vector is heavily dependent on the specific therapeutic program. “There isn’t a universally effective or better way to deliver a therapy, either viral or non-viral,” Wang said. He noted, for example, that viral vectors remain a good choice when long-term gene expression is desired. And for viral vectors, the manufacturing process might be more mature, easing transfer to a contract development and manufacturing organization.
However, Wang cautioned that viral vectors still present certain safety concerns. “In recent years, an increasing number of scientists and the FDA have recognized these risks,” he said, “leading to a surge in interest for non-viral delivery methods—particularly for in vivo CAR T therapy and gene editing.”
GenScript has provided LNP services to several customers globally. The most advanced of those is using GenScript’s GMP CRISPR materials (gRNA, HDR templates, and nuclease) alongside a customized LNP encapsulation recipe and is preparing an investigational new drug application.
Foundational LNP science
Vancouver-based Genevant traces its scientific lineage through a string of predecessor companies dating back to the early 2000s and controls foundational intellectual property for the field. Based on its scientists’ work at Protiva Biotherapeutics, the intellectual property comes to Genevant via Arbutus Biopharma, which acquired Protiva in 2015 and partnered with Roivant in 2018 to establish Genevant.
Unlike many companies developing nucleic acid delivery platforms that focus on a single payload modality, Genevant has applied its LNP to many payloads, including mRNA, siRNA, and gene editors in fields spanning antiviral, oncology, and metabolic disorders. The firm’s LNP platform is part of the first RNA-LNP product to achieve regulatory approval, Alnylam Pharmaceuticals’ Onpattro (patisiran), a treatment for polyneuropathy in people with hereditary transthyretin-mediated amyloidosis. Genevant’s LNP technology is also behind Moderna’s COVID-19 vaccines, which were confirmed earlier this month with the resolution of a longstanding patent dispute. An infringement case against Pfizer and BioNTech is pending. Genevant collaborated with Chula Vaccine Research Center and the University of Pennsylvania to develop a COVID vaccine for low- and middle-income countries in Southeast Asia during the pandemic. The program had success, demonstrating non-inferiority to Pfizer and BioNTech’s Comirnaty in clinical trials.
Some key differentiators for Genevant’s LNPs include strategies for optimized delivery in non-human primates instead of mice,2 which has resulted in improved gene editing in the liver, and novel chemistries for biodegradable LNPs that prevent accumulation in tissue.3 The company has recently disclosed data showing targeted delivery to T cells for in vivo CAR T therapy, as well as hematopoietic stem and progenitor cells (HSPC) and hepatic stellate cells.
References
- Skeate JG, Pomeroy EJ, Slipek NJ, et al. Evolution of the clinical-stage hyperactive TcBuster transposase as a platform for robust non-viral production of adoptive cellular therapies. Mol Ther. 2024;32(6):1817-1834. doi:10.1016/j.ymthe.2024.04.024
- Lam K, Schreiner P, Leung A, et al. Optimizing lipid nanoparticles for delivery in primates. Adv Mater. Published online March 27, 2023. doi: 10.1002/adma.202211420
- Holland, R, Lam K, Jeng S, et al. 2024. Silicon ether ionizable lipids enable potent MRNA lipid nanoparticles with rapid tissue clearance.” ACS Nano. 2024;18 (15): 10374–87. doi:10.1021/acsnano.3c09028.
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Breaking Through the Barrier
According to the American Brain Foundation, over one in three people around the world are affected by neurological conditions, the leading cause of illness and disability worldwide. This silent epidemic is not country-specific. Neurological conditions such as lysosomal storage disorders, rare enzyme deficiencies, and Alzheimer’s and Parkinson’s disease take their victims, regardless of age, race, or location.
For decades, scientists have struggled to deliver therapeutics to the brain, only to be thwarted by the highly protective blood-brain barrier (BBB). First-generation approaches demonstrated proof of principle but still require advancements to improve the ability to reach specific areas of the brain, or specific cell types, safely, and with sufficient dosage to enable meaningful therapeutic effects.
Although much remains unknown generally about brain biology and its defensive mechanisms, novel therapies for devastating neurological diseases are progressing into clinical trials. There is no magic bullet—no promises, no cures—but a gleaming light can be seen in this particular long and dark tunnel.
Dedicated scientists continue to work on gene therapies for the indications that most benefit from a once-and-done approach, in addition to neurological shuttles to address those disorders that require therapeutic tempering and dosage control.
Expanding platform technologies
In 2021, JCR Pharmaceuticals received regulatory approval for the first biotherapeutic, IZCARGO
(pabinafusp alfa), designed to cross the BBB to deliver a therapeutic enzyme for the treatment of a lysosomal storage disorder called mucopolysaccharidosis type II (MPS II) or Hunter syndrome.
The platform technology has been expanded to exploit receptor-mediated transcytosis (RMT) to address other lysosomal storage and neurodegenerative diseases. Still, delivery to specific cells or parts of the brain remains challenging, along with efficient delivery of antisense oligonucleotides or siRNA.
“The issue is not delivery across the BBB, but the endosomal escape to efficiently suppress the target RNA,” said Hiroyuki Sonoda, PhD, representative director, president, and CSO, at JCR Pharmaceuticals. “Small molecule CNS delivery is related to physicochemical properties. The structural design needs to make them lipophilic, yet also able to evade typical transporter clearing mechanisms.”
J‑Brain Cargo® uses RMT, mainly focusing on the transferrin receptor (TfR). Other promising candidates target different receptors. “We have successfully transported enzymes, antibodies, peptides, decoy receptors, antisense oligos, and siRNA into the CNS,” commented Sonoda. J‑Brain Cargo is particularly suited for enzyme replacement therapies in lysosomal storage disorders and conditions where dose control, reversibility, and titration are important.
For gene therapies, JCR developed the JUST-AAV platform technology. Novel changes in the capsid almost completely eliminate liver tropism. The modified capsids express miniaturized antibodies on the capsid surface against receptors on selected tissues, organs, or the BBB, enhancing targeted delivery. JUST‑AAV is for diseases where continuous transgene expression is desired to achieve the optimal effect.
Several candidates are in global clinical trials, including JR-141 (pabinafusp alfa) for individuals with MPS II (also known as Hunter syndrome), JR-171 to treat MPS I (also known as Hurler, Hurler Scheie, or Scheie syndromes), and JR-441 for individuals with MPS IIIA (also known as Sanfilippo syndrome A).
Programs in collaboration with MEDIPAL HOLDINGS CORPORATION are in different stages of clinical and pre-clinical development for individuals with MPS IIIB (also known as Sanfilippo syndrome B), Fucosidosis, and GM2 gangliosidosis (including Tay-Sachs and Sandhoff disease).
Collaborating with leading pharmaceutical companies is core to JCR’s strategy to bring these platform technologies to broader application. “We enable our partner by turning their biologics into CNS-penetrating versions of their original molecule,” said Sonoda.
JCR manufactures most of its drug products in-house. Last year, they were selected for the Ministry of Economy, Trade and Industry’s “Regenerative CDMO Subsidy” to expand biomanufacturing capacity for regenerative, cell, and gene therapies.
Optimizing BBB transport
“Protein engineering architecture differentiates our delivery technology along with its optimization for efficacy, safety, and tolerability,” said Ryan Watts, PhD, co-founder and CEO of Denali Therapeutics.
The TransportVehicle (TV) technology has the RMT binding site integrated directly into the constant domain (Fc) of an antibody for optimal properties and modularity. This allows the same TV sequences to transport a range of large molecule biotherapeutics such as enzymes, oligonucleotides, and antibodies for systemic administration. The engineered Fc domains bind to specific natural transport receptors expressed at the BBB, such as TfR.
“Our research recently demonstrated that a TV platform-enabled anti-Ab antibody improved distribution in the brain and significantly reduced risk of Amyloid-Related Imaging Abnormalities (ARIA) in a mouse model of Alzheimer’s disease, when compared with a conventional anti-Ab antibody.1 The study provides the first mechanistic insight for mitigating the risk of ARIA,” detailed Watts.
The Enzyme TransportVehicle (ETV) contains a fusion of a therapeutic enzyme. The Fc portion of the fusion molecule binds the apical surface of the TfR to avoid interference with normal iron transport.
In March 2026, Denali’s lead ETV program, Avlayah (tividenofusp alfa-eknm), received FDA accelerated approval for the pediatric treatment of the lysosomal storage disorder MPS II. Avlayah is the foundation for their broader ETV franchise, addressing other lysosomal storage disorders such as MPS IIIA. Results from the open-label Phase I/II clinical trial are available.2
Their Oligonucleotide TransportVehicle (OTV) platform is an engineered TV conjugated to an oligonucleotide for the systemic delivery of genetic medicines to the brain. Extensive characterization and research demonstrate the ability of OTV to elicit broad biodistribution of oligonucleotide therapies throughout the CNS following systemic exposure.
“For example, our investigational therapy DNL628 for the treatment of Alzheimer’s disease is designed to cross the BBB and reduce the tau protein by targeting the MAPT gene that encodes for tau,” explained Watts.
Lastly, the Antibody TransportVehicle (ATV) platform is designed to enable brain delivery of antibodies capable of selective immune activation and a targeted therapeutic approach after intravenous administration. The investigational anti-Ab antibody therapy DNL921, for example, is designed to reduce amyloid plaques and avoid ARIA.
The TV-enabled clinical development portfolio also includes candidates for frontotemporal dementia-granulin and Pompe disease.
Advancing clinical options
“It is exciting to begin to see that delivery through the BBB is possible using gene therapy or shuttle approaches,” said Todd Carter, PhD, CSO at Voyager Therapeutics. Although first-generation therapeutics are demonstrating meaningful levels of delivery, optimization, and improvement of the functionality, exposure duration, and therapeutic effects are still needed.
“For some diseases, gene therapy is the preferred treatment modality, as both the capsid and the payload can be modified to perform a specific job,” said Carter. But viral vector delivery for gene therapy has had problems with liver-based toxicity.
For the best human translation opportunities, Voyager developed a model in non-human primates (NHPs) requiring cross-species activity across multiple NHP species. This strategy resulted in the company’s TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA) technology, used to screen tens of millions of vector variants using barcoded libraries in which capsids were modified with slight insertions of seven to nine amino acids.
Successful expression in neurons demonstrated that the capsids crossing the BBB worked. Directed evolution improved them. “Next, we needed to determine the mechanism—the receptors they were targeting,” said Carter. This led to the identification of the receptor, alkaline phosphatase (ALPL), tissue nonspecific.
Now, Voyager has multiple families of capsids that mediate delivery into the brain, are detargeted from the liver, and, for the most advanced, have improved the capsid’s ability to target the brain using ALPL. “Using the ALPL receptor elevates delivery to the brain and allows us to substantially reduce dosage,” said Carter.
“I would not have picked ALPL just on face value,” added Mihalis Kariolis, PhD, vice president of non-viral therapeutics at Voyager Therapeutics. “It highlights the power of the unbiased TRACER approach. Expanding the number of brain delivery receptors provides highly differentiated options to reduce side effects and expand the diversity of treatment modalities.”
Both gene therapy and shuttle approaches have opportunities in different indications. Once-and-done gene therapy is not tweakable, whereas shuttle-based dosing is. “In our APOE gene therapy program, we want to reduce existing APOE4 and replace it with APOE2 permanently,” said Carter. “The shuttle has advantages in situations where permanent ongoing delivery is not required.”
Voyager’s most advanced program (VY7523) is a tau monoclonal antibody that is exquisitely specific for pathological tau. Data will be available in the second half of the year. A gene therapy (VY1706) moving into the clinic this year is designed to knock down tau mRNA and protein intracellularly. A collaboration with Neurocrine Biosciences focuses on Friedreich’s ataxia (FA) and is also expected to enter the clinic this year.
Combining transport receptors
The protective BBB is crucial for maintaining homeostasis and ensuring proper neurological function. Comprised of both cellular and acellular components, this sophisticated structure tightly regulates information flow between the periphery and the brain. According to Tanya Wallace, PhD, vice president of neuroscience discovery research at AbbVie, despite the BBB’s importance, many seemingly basic biological questions remain unanswered, fueling additional global research.
The complexity of the BBB also represents a significant bottleneck for advancing therapeutics targeting brain-related disorders. Historically, achieving therapeutically relevant levels of drugs in the brain has been a major challenge in treating serious diseases such as Alzheimer’s and Parkinson’s diseases. “A notable success story is the development of L-DOPA, a prodrug that leverages existing transport mechanisms to cross the BBB,” said Wallace. Once in the brain, L-DOPA is metabolized into dopamine, offering a key symptomatic treatment for Parkinson’s disease.
Breakthroughs in delivery now allow scientists to leverage more technologies that can bring not only small molecules but also complex biologics into the brain. The Modular Delivery (MODELTM) platform exemplifies this progress. The platform enables engineering of bispecific antibodies, capable of targeting naturally expressed BBB receptors such as TfR and CD98. TfR and CD98 are well-characterized at the BBB, and, together, they offer distinct advantages for increasing brain exposure to therapeutics.
“By engaging these transport pathways, the platform can enhance the uptake of a variety of therapeutics, including antibodies and oligonucleotides,” highlighted Wallace. “This multi-receptor strategy provides flexibility to optimize the balance of uptake, release, and distribution in the brain, paving the way for potentially more effective treatments across neurological disease areas.”
This platform technology facilitated the development of ABBV-1758, which is progressing in clinical development. ABBV-1758 utilizes TfR to transport a 3pE-Ab antibody across the BBB to enable the removal of amyloid beta plaques, a pathological hallmark of Alzheimer’s disease.
As scientists aspire to further refine delivery strategies, ongoing research is exploring additional receptors and innovative approaches, including insulin-like growth factor 1 receptor (IGF-1R) and brain cell-type-specific targeting. The field is rapidly evolving to advance more precise, personalized interventions for challenging neuroscience conditions.
“Successful brain delivery requires more than just advances in transport technology; it demands interdisciplinary collaboration, novel preclinical models, and thoughtful clinical translation,” Wallace pointed out. Continued biological research and investment into innovative discovery platforms will be crucial for bringing transformative therapies to patients with the greatest unmet needs.
References
- Pizzo ME, Plowey ED, Khoury N et al. Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA. Science. 2025 Aug 7;389(6760):eads3204. doi: 10.1126/science.ads3204.
- Muenzer J, Burton BK, Harmatz P et al. An intravenous brain-penetrant enzyme therapy for mucopolysaccharidosis II. N Engl J Med. 2026 Jan 1;394(1):39-50. doi: 10.1056/NEJMoa2508681.
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Rewriting the Rules of CAR T Delivery
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The next evolution of CAR T therapy isn’t happening in a cleanroom—it’s happening inside the patient. For years, ex vivo CAR T has defined the field: extract T cells, engineer them, reinfuse them. This is effective, but complex, time-intensive, and logistically demanding. Each step introduces variability, from cell handling to expansion efficiency, while requiring specialized infrastructure that can limit scalability. In contrast, in vivo CAR T is gaining traction as a more streamlined alternative, especially by using lentiviral vectors (LVVs) to deliver genetic instructions directly into the body.
“By being able to produce CAR T cells directly in the body, you mitigate a lot of the room for error,” explains Annie Huang, senior manager of content marketing at GenScript ProBio. “Without dealing with cell culture and all the associated handling, you reduce variability and complexity.”
CAR T therapy works by equipping T cells with engineered receptors that recognize and attack disease. Traditionally, that engineering happens outside the body through a multi-step workflow that can take weeks. In vivo approaches eliminate those steps by delivering genetic material directly to T cells, enabling them to be reprogrammed in place.
This shift is not just about efficiency. By reducing reliance on external processing, in vivo CAR T has the potential to improve consistency and expand access for patients who might not be able to wait for or access complex manufacturing pipelines. Expanding the development and testing of in vivo CAR T therapies, though, depends on giving
researchers and companies easy access to the tools they need.
Why ProBio’s tLVV platform stands out
ProBio is advancing the field with a purpose-built LVV platform designed specifically for in vivo CAR T applications, “known as tLVV—a T cell binder present on the LVV envelope, which serves as a ‘T cell specifically targeting LVVs’ or ‘T cell re-targeting LVVs’.” says Huang. “Our tLVV platform optimizes membrane fusion capability, which leads to higher functional titers and maximized transduction efficacy.” The system integrates a proprietary transfer plasmid backbone with customer-provided binders and fusogens. The binder acts as a targeting mechanism, directing where the viral particle attaches, while the fusogen enables entry into the desired cell. This modular approach allows developers to tailor targeting strategies while leveraging ProBio’s optimized backbone and supporting plasmid systems.
Importantly, ProBio’s platform is engineered to address a key concern in in vivo delivery: off-target effects. By incorporating a proprietary backbone designed to silence unintended CAR expression, the system helps reduce the risk of incorrect binding and antigen masking—issues that can compromise efficacy or lead to resistance. This design focus supports more controlled and efficient transduction in vivo.
LVVs also offer a significant advantage in terms of acceptance by regulators. “From a regulatory perspective, LVV is more mature,” says Jingyuan Zhang, PhD, content marketing specialist at ProBio. “So, there’s less barrier when applying it to in vivo approaches.”
Because LVVs are already widely used in ex vivo CAR T therapies, they come with an established safety and manufacturing track record. This familiarity can help streamline regulatory pathways, allowing developers to focus innovation on delivery and targeting rather than introducing entirely new vector systems.
From design to scaled delivery
Once administered, the LVV delivers CAR genes directly into T cells, initiating an immune response against disease targets. However, achieving reliable performance in vivo requires overcoming challenges such as envelope protein variability, vector aggregation, and binding inefficiencies.
ProBio addresses these issues through optimized plasmid design, refined manufacturing workflows, and integrated development services that support consistency from early-stage research through clinical production. The company’s new facility in Hopewell, New Jersey, further strengthens this capability, providing scalable viral-vector manufacturing tailored to in vivo CAR T and gene therapy applications. This facility can also manufacture non-viral versions of gene therapy.
Combined with end-to-end support—from construct design to CMC and GMP production—ProBio’s tLVV platform positions developers to move more efficiently from concept to clinic. As in vivo CAR T continues to evolve, such integrated solutions may play a crucial role in translating promise into practical, accessible therapies.
Explore More: www.probiocdmo.com/webinars/gene-cell-therapy-categories
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Inexpensive seafloor-hopping submersibles could stoke deep-sea science—and mining
Smack dab between Australia and South America, the US National Oceanic and Atmospheric Administration (NOAA) research vessel Rainier is currently on a mission to map more than 8,000 square nautical miles of the Pacific seafloor in search of critical mineral deposits. But it isn’t doing it alone; for a month starting this week, it will deploy two oblong neon submersibles as the project’s special agents, sending them nearly 6,000 meters down to hop along the seafloor.
The submersibles, built by the young company Orpheus Ocean, are designed to explore just this environment: a squelchy substrate that teems with life of all kinds, from tiny microbes to worms and snails, along with egg-size “nodules” of metals—such as copper, cobalt, nickel, and manganese—that are crucial for technologies worldwide.
Scientists and companies have long sought to probe the deep sea and bring such treasures to the surface. Orpheus, which spun off from the Woods Hole Oceanographic Institution (WHOI) in 2024, could be well positioned to make those possibilities a lot more economical. The company has designed its vehicles on a simple philosophy: “deep for cheap,” says Jake Russell, Orpheus’s cofounder and CEO, who is a chemist by training. The vehicles cost a couple of hundred thousand dollars each to build, whereas existing options can range from $5 million to $10 million. And unlike most autonomous ocean vehicles, they can push into the seafloor and capture cores of sediment—and the creatures within.
Orpheus’s engineers have been tinkering with their deep-sea designs for years, much of the work taking place at WHOI and in collaboration with NOAA and the National Aeronautics and Space Administration. Its prototype vehicles were rated capable of diving to 11,000 meters—the deepest part of the Mariana Trench. They’ve completed two commercial deployments, but this new expedition marks the submersibles’ biggest test yet: operating over large ranges for multiple weeks and with multiple instruments at play. Using Rainier as their home base on the ocean’s surface, the vehicles will swim out for 10 kilometers at a time, taking one high-resolution image every second and up to eight physical samples from the seafloor apiece.
If all goes well, the test could help establish the vehicles as a tool for government agencies, scientists, and companies that hope to probe the vastly understudied deep sea and the resources it holds. And while they’re not the only option on the market, Orpheus hopes their size and low building cost will soon make them one of the most accessible.
At present, to reach these depths scientists must wait for time on a limited and expensive set of submersibles owned by government agencies and research institutes. That formula lends itself better to capturing snapshots of the deep sea than it does to probing its interconnected ecological and biogeochemical systems. “A lot of this region that we’re surveying … has really never been explored in any kind of detail,” says Russell. “Anything we see is going to be new to NOAA and new to science.”
A sediment specialist
The Orpheus subs are classified as autonomous underwater vehicles (AUVs), which operate on a mix of preprogrammed commands and live decision-making and without being tethered to a ship. But unlike traditional AUVs engineered for long-distance, high-speed gliding, these submersibles are short and stout with little legs—better for making soft landings on the seafloor and then pushing into the mud to suck out sediment cores for scientists. When they do land, the submersibles can lift off the surface, thrust a few feet, and settle once more in a “hopping” fashion.
Their bodies are made mostly of a buoyant material known as syntactic foam, with the important electronics encased in a thick sphere of glass. The same kind of foam, which is interspersed with hollow microspheres of glass to prevent it from collapsing under high pressures, went to the deep in the vehicle that carried the filmmaker James Cameron to the Mariana Trench in 2012; he even donated leftover material for use in earlier Orpheus prototypes.
At less than two meters in length and under 600 pounds (270 kilograms), Russell says the Orpheus robots are the smallest—and correspondingly the least expensive—ocean vehicles on the market capable of descending to 6,000 meters. They’re designed to populate future fleets of robotic explorers.
The approach stems from a fundamental challenge, says Victoria Orphan, a geobiologist at the California Institute of Technology, who has previously worked with an Orpheus vehicle on a science campaign: “Anytime you do things in the deep ocean, you always run this risk, when you put something over the side [of a ship], that it might not come back.” With existing fleets of large, expensive vessels operated by groups like NOAA, WHOI, and the Monterey Bay Aquarium Research Institute (MBARI), losing a vehicle can be disastrous, not least because scientists must already compete for their limited time.
In the spring of 2024, Orphan and her colleagues put an Orpheus sub through its paces during an expedition to study deep-sea methane seeps off the coast of Alaska’s Aleutian Islands. They hoped to use the vehicle to create maps of the area before the team sent down a human-crewed submersible called Alvin to study specific areas—and the microorganisms and animals that live there—in more detail.
But as with any sort of new type of technology, “there’s always growing pains,” recalls Orphan. Frigid temperatures and steep topography added unseen challenges, and it took the full three weeks for the sub to get high-resolution photographs of the seeps.
The setback didn’t dull Orphan’s excitement about the potential of these machines. “There’s a lot of real, unknown science right at that interface between the sediment and the ocean surface,” she says. “The Orpheus-type class of instrument, with the right kinds of sensors and samplers, could be a very enabling tool.”
Russell envisions pairing the vehicles with specially designed payloads that can sense the heat of chemical seeps and detect plumes of sediment, DNA shed from ocean life-forms, or the magnetic tug of buried cables.
The vehicles are the “the best of both worlds,” says Andrew Sweetman, a deep-sea ecologist at the Scottish Association for Marine Science, who has not worked with Orpheus. While they can roam large areas like an AUV, they can also carry out precise sampling maneuvers like a remotely operated vehicle (ROV), a robot connected to a ship via cables that fulfills real-time human commands.
In addition to the low price tag, says Sweetman, the small size of the vessels means they don’t require a large research vessel to ferry them out to sea. That might make exploration more accessible for smaller or poorer countries without such ships, he says: “It will, in a way, help democratize deep-sea science.” He imagines using the sediment cores the submersibles gather to probe how seafloor-dwelling animals cycle nutrients—a crucial element of the ocean’s role as a carbon sink.
The mining push
As much as smaller, cheaper ocean vehicles have caught scientists’ eye, they have also piqued the interest of companies. Russell says inquiries come in weekly from businesses involved in deep-sea mining, defense, offshore wind, telecommunication, and oil and gas. He notes that Orpheus is merely a “service provider,” helping collect data where needed but not making decisions about how to use the seafloor. And he says that better data—such as information on the shape of the seafloor, the sediment quality, and the presence of life—also “raises the bars” that governments and regulators are only beginning to set.
But many scientists are far from eager about the growing push for seabed mining, which an executive order from President Donald Trump stoked further last week by mandating that the US government rapidly develop mineral exploration and processing. And earlier last month, the administration announced the creation of a new government office: the Marine Minerals Administration.
ORPHEUS OCEAN
Given the current dearth of information on the deep sea, says Sweetman, “I think the push for deep-sea mining is happening way too fast.” And deep-sea communities are “probably the most stable environment on our planet,” adds Orphan. “The organisms that live there are really not adapted to a lot of disturbance, and it takes a really, really long time for them to recover, if at all.”
One mining method that governments and companies propose involves a machine that essentially operates like a giant bulldozer, trawling the seafloor, sucking up a trail of material, and leaving scar marks and sediment plumes in its wake. Brett Hobson, an ocean engineer at MBARI, says that Orpheus-like technology might enable companies to “take samples in a more surgical way, instead of just grossly scooping everything up off the seafloor and filtering through it.”
Hobson, who has run MBARI’s work on ocean vehicles for decades, also notes that Orpheus submersibles won’t be the only option available. Companies and government agencies—including those in Norway, France, Japan, China, and the UK—are developing similar deep-sea vehicles, he says: “What we really need [as] a society is just more of these systems out there.”
As Orpheus’s neon vehicles plunge into the Pacific over the next few weeks, their readiness for future scientific and resource surveys should become clearer. Each time they dive, they will get a little bit more data—“just the smallest of postage stamps of our planet,” says Orphan. “There’s still so much to learn.”
Trump’s mass firing just dealt another blow to American science
This past week delivered another gut punch for science in the US. This time, the target was the National Science Foundation—a federal agency that funds major research projects to the tune of around $9 billion. The foundation’s efforts were overseen by a board of 22 prominent scientists. On Friday last week, they were all fired.
The NSF has been without a director since April 2025, when former director Sethuraman Panchanathan stepped down in the wake of DOGE-led funding cuts and mass firings. Trump’s nominee for the role is Jim O’Neill, an investor and longevity enthusiast who does not have a science background.
It’s hard to predict exactly how things will shake out for science. But it’s not looking great.
The NSF was established in 1950 to “promote the progress of science,” among other goals. It has served as a major source of support for research and education since then. In 2024, the agency spent $9.39 billion—a substantial figure but only 0.1% of all federal spending.
Key decisions about how that money is spent have been made by the National Science Board. Each of the scientists who made up the board until last week was appointed by a US president to serve, at least initially, a six-year term. Those members were responsible for establishing NSF policies, authorizing major expenditures and providing oversight, says Keivan Stassun, a physicist and astronomer at Vanderbilt University who was appointed to the board in late 2022.
A few years ago, the board was responsible for establishing a new “directorate” within the agency to channel funding to “technology, innovations and partnerships,” for example. The board also authorized funding for the US Extremely Large Telescope Program.
“It’s a relatively small group with a tremendous amount of responsibility and authority,” says Stassun. He viewed his appointment as “a tremendous honor.”
Then, last Friday, the email landed in his inbox. “It said: On behalf of President Trump, this letter is to notify you that your position as a member of the National Science Board is terminated effective immediately. Thank you for your service,” says Stassun. “It was deeply disappointing.”
Still, Stassun wasn’t surprised, given the administration’s actions across federal science agencies over the past year.
Since Donald Trump took office at the start of 2025, the NSF—along with many other federal agencies—has frozen, unfrozen, and terminated grants. “The board was not involved in any of those [terminations],” says Stassun. Members had no say in the firing of agency staff either, he says. Staff numbers are currently down 40%, he adds.
In a 2026 budget request, the Trump administration sought to cut the NSF’s budget by around 57%. Last summer, NSF staffers wrote a letter of dissent arguing that such substantial cuts would “cripple American science.” The proposed cuts would have hit biological sciences, engineering, and STEM education particularly hard.
Those cuts were rejected by Congress earlier this year. But grant terminations and firings are essentially allowing them to take effect regardless, says Stassun. “The funds that the White House has been dispersing to the agency … have been far less than what Congress intended,” he says.
Many ambitious research projects are grinding to a halt as a result. “The Extremely Large Telescope Program appears to be dead in the water for now,” says Stassun. And the NSF arm dedicated to science education “has effectively zeroed out,” he says.
But not all of them. While the administration’s 2027 budget request states that NSF will “close out” its directorate for social, behavioral, and economic sciences, it describes AI and quantum information science as key “frontier initiatives.” Biotechnology is described as a “focal point.”
When asked for comment, the NSF directed MIT Technology Review to the White House press office. The White House did not respond directly to questions about the firing of NSB members and said in a statement, “The National Science Foundation’s work continues uninterrupted.”
Jim O’Neill, Trump’s current candidate for the position of NSF director, is certainly interested in biotechnology. Specifically, when I spoke to O’Neill in February, he told me that he supposes he is a Vitalist—a hardcore supporter of efforts to extend human longevity who believes that death is wrong.
O’Neill was deputy secretary of the Department of Health and Human Services and acting director of the Centers for Disease Control and Prevention until a leadership shakeup a couple of months ago. But he isn’t a scientist. And that has some scientists worried. He has yet to be confirmed by the Senate for the role.
In the meantime, the administration’s efforts are having a real impact on research. “We [NSB members] tried to stand for a continued investment in science, engineering, and technology, and in science education broadly,” says Stassun. “The administration will now be able to operate the agency the way that [it wants to, with] no governance body in the way.”
Opinion: The psychedelic revolution is leaving behind people of color
Flanked by one of psychedelics’ biggest celebrity cheerleaders, Joe Rogan, and a troupe of MAHA loyalists, President Trump recently signed an executive order aimed at accelerating psychedelic access for clinical research and treatment.
Use of naturally occurring and synthetic hallucinogens traces back to the Neanderthals. Yet these substances have long been a pariah in mainstream medicine, written off as “club drugs” with little to no clinical value (or worse, downright negative effects).
Current Landscape of Mental Health Conversational Agents From a Trauma-Informed Care Lens: Scoping Review
Background: Conversational agents (CAs) are increasingly used in mental health care to enhance access and engagement. However, their safe, ethical, and user-sensitive design remains a challenge. Despite growing attention to trauma-informed approaches in human-computer interaction, there is limited work on how the trauma-informed care (TIC) framework could be applied in the design of mental health CAs and no comprehensive synthesis to date. Objective: Guided by the Substance Abuse and Mental Health Services Administration’s TIC framework, this scoping review explored how TIC principles (safety; trustworthiness and transparency; collaboration and mutuality; empowerment, voice, and choice; peer support; and cultural, historical, and gender issues) are currently represented in the design and evaluation of mental health conversational agents (MHCAs) and identified gaps and opportunities to promote more trauma-informed design practices. Methods: Online databases, as well as a secondary survey of citation lists from an initial search, were used to identify English-language journal articles and conference proceedings from 2000 to 2024 that empirically evaluated an independent, web- or app-based, unassisted CA used for mental health and included concepts from TIC. Results: Our analysis included 38 publications (n=28, 73.7%, published in 2020 or later) covering 28 distinct MHCAs. Most studies used experimental methods (n=23, 60.6%) or user studies (n=11, 28.9%), with samples skewed toward female (men: mean 34.92%, SD 18.64%), young in age (mean 32.52, SD 14.6 y), and predominantly nonclinical (n=29, 76.3%). MHCAs were largely rule-based prototypes. No studies explicitly referenced the TIC framework as a guiding lens for MHCA design or evaluation. A total of 26 studies referenced terminology from TIC core principles but rarely defined them, while all 38 included language that could be linked to one or more principles. Overall, TIC-related concepts appeared most often within intervention design descriptions, qualitative assessments, or as items embedded in questionnaires evaluating broader constructs. Trustworthiness and transparency, safety, empowerment, voice and choice, and collaboration and mutuality were comparatively well addressed, while peer support and cultural, historical, and gender issues were largely absent. Design recommendations, where present, were relatively broad and emphasized secure, customizable, reliable, human-like, and context-sensitive MHCAs that offered multimodal interaction, goal setting and tracking, and transparency. Conclusions: Studies did not self-identify as using Substance Abuse and Mental Health Services Administration’s framework for TIC, making it more difficult to identify its elements. The fragmented terms, disciplines, and metrics used make it difficult to draw more systematic conclusions about the current research landscape related to TIC, but our analysis indicates TIC to be a descriptive and potentially unifying framework and provides a starting point for the explicit trauma-informed MHCA research and design.
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