Disrupting Semaglutide? Tsinghua University Develops Long-Lived CAR-T Cells for Single-Dose, Long-Term Prevention and Treatment of Obesity and Diabetes

Biologics (especially recombinant proteins) are the cornerstone of modern biomedicine. Although recombinant proteins have shown remarkable efficacy in treating various diseases, their short in vivo half-life is a major limitation. Using engineered cells as a delivery platform for biologics may overcome this challenge.

Because chronic diseases are progressive and often irreversible, protein-based drugs usually require long-term (even lifelong) repeated injections to maintain therapeutic effects. For example, GLP-1 drugs such as semaglutide and tirzepatide have completely transformed the treatment of diabetes and obesity. However, as peptide biologics, they require weekly injections, and the effect only persists with continuous use; once discontinued, the lost weight quickly rebounds.

Moreover, repeated administration of peptide/protein biologics may trigger anti-drug immune responses. Once anti-drug immunity forms, further injections may reduce efficacy or even become ineffective, and can also cause immunopathological issues. Therefore, for biologics treating chronic diseases, a single-dose, long-acting therapy is more ideal.

On August 29, 2025, the team led by Peng Min at the Institute of Immunology, Tsinghua University, published a research paper in the Nature sub-journal Nature Communications titled "GD2TIF cells as a platform for single-dose and long-term delivery of biologics".

The study developed long-lived CAR-T cells as a novel in vivo drug delivery platform. These long-lived CAR-T cells achieved stable, long-term delivery of the GLP-1 drug for treating obesity and diabetes in animal models. A single administration was sufficient to maintain long-term remission, providing potential curative possibilities for chronic diseases that require lifelong treatment.

Strategies for Achieving "Single-Dose, Long-Lasting" Therapy

To achieve the goal of "one-time treatment, long-lasting effect," researchers have proposed and tested multiple strategies, verified in animal models and clinical trials. For example, adeno-associated virus (AAV) vectors can deliver DNA encoding therapeutic proteins, such as factor IX (FIX) in hemophilia or HIV-neutralizing antibodies in AIDS. However, because AAV vectors cannot integrate into the genome, injected AAV gradually decays over time, usually lasting less than two years. Therefore, AAV-based biologics delivery cannot provide long-term efficacy.

Recently, immune cells, including chimeric antigen receptor T (CAR-T) cells, have been engineered to secrete therapeutic proteins. However, in previous studies, these immune cells were limited in number and short-lived, making them unsuitable for long-term biologics delivery.

In recent years, cell therapies represented by CAR-T cells have shown "curative" effects in relatively rare diseases like hematologic tumors and autoimmune disorders. Compared with traditional drugs, CAR-T cells are "living" drugs capable of self-replication and persistence in patients, which could potentially achieve "single treatment, long-lasting effect."

In March 2024, Peng Min’s team published a study in the Journal of Experimental Medicine titled "Induction of immortal-like and functional CAR T cells by defined factors". The study used multiple gene edits to knock out BCOR and ZC3h22A, constructing long-lived T cells—immortal-like and functional T cells (TIF cells). TIF cells can persist safely in vivo and achieve long-term tumor remission, potentially solving the problem of tumor relapse caused by CAR-T cell loss. Human clinical trials are currently ongoing.

In May 2025, the team published a paper in Nature Immunology titled "A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice". 

This study further engineered TIF cells to express IL-5 on the cell membrane and secrete IL-4 mutants (named 5TIF4 cells). These cells could target and clear eosinophils that trigger allergic reactions. A single injection could durably suppress signs and symptoms of allergic asthma in mice, providing a potential therapy for long-term remission of allergic asthma and similar diseases.

Requirements for CAR-T Cells as a Platform for Chronic Disease Biologics Delivery

Three prerequisites must be met to make CAR-T cells a practical delivery platform for biologics in chronic diseases:

1. Chemotherapy-based preconditioning used in current autologous CAR-T therapies must be abandoned, as chemotherapy is unsuitable for non-cancer patients.
2. CAR-T cells must persist in vivo at sufficient numbers, ideally for life, because most chronic diseases are lifelong.
3. CAR-T cell targets must be carefully chosen to avoid damage to normal cells or tissues.

Based on these considerations, Peng Min’s team selected the GD2 target, a tumor-associated antigen overexpressed in neuroblastoma but minimally expressed in normal tissues. Moreover, GD2-targeting CAR-T cells have demonstrated good clinical efficacy with minimal off-target effects. The team then constructed long-lived GD2-targeting CAR-T cells—GD2TIF cells. These GD2TIF cells could robustly expand in immunocompetent mice without chemotherapy preconditioning, demonstrated good safety, and persisted long-term in vivo.

In the latest study, the research team repurposed GD2TIF cells as a universal platform for long-term in vivo delivery of biologics, aiming to achieve long-term therapeutic effects with a single injection of CAR-T cells.

The team used GD2TIF cells to deliver GLP-1 long-term. In high-fat diet-induced obese mice, a single infusion of GLP-1-secreting GD2TIF cells (GD2TIF-GLP-1 cells) maintained normal body weight and blood glucose levels over the long term, achieving "curative" benchmarks for diabetes and obesity prevention and treatment, without observed side effects.

Conclusion

Overall, the study successfully engineered GD2TIF cells into a reliable in vivo platform for stable biologics production, validating their potential for long-term GLP-1 delivery to prevent and treat diabetes and obesity. This approach offers a "single-dose, long-lasting" cell therapy for chronic diseases that typically require repeated injections. Importantly, as many diseases are treated with biologics, this research may provide one-time solutions for multiple conditions.

The research team noted that although CAR-T therapies remain expensive, as cell therapy costs decrease, long-term biologics delivery via CAR-T cells will likely be more cost-effective than repeated injections. Most importantly, this one-time solution allows patients to live normal lives without continuous medication or frequent hospital visits.

References

[1]. https://www.nature.com/articles/s41467-025-63427-w

[2]. https://doi.org/10.1084/jem.20232368

[3]. https://www.nature.com/articles/s41590-024-01834-9