Johns Hopkins Scientists Develop Biodegradable Nanoparticles to Generate CAR-T Cells Directly in the Body

Mar,11 2026- Researchers at Johns Hopkins Medicine have developed a simplified biodegradable nanoparticle platform capable of generating CAR-T cells directly inside the body, potentially offering a more accessible alternative to traditional cell therapy manufacturing.

The study, published in Science Advances, describes targeted polymeric nanoparticles (tPNPs) that deliver mRNA encoding an anti-CD19 chimeric antigen receptor (CAR) into immune T cells. Once programmed, these T cells recognize and eliminate B cells, which are responsible for diseases such as lupus and B-cell cancers including leukemia and lymphoma.

The research was led by Jordan Green, Ph.D., professor of biomedical engineering at the Johns Hopkins University School of Medicine.

Toward in vivo CAR-T generation

Conventional CAR-T therapies require extracting a patient’s T cells, genetically engineering them in specialized manufacturing facilities, and reinfusing them into the patient. This complex ex vivo manufacturing process contributes to the high cost and limited accessibility of current CAR-T treatments.

The Johns Hopkins team aims to bypass these steps by programming T cells directly inside the patient using nanoparticles that carry therapeutic genetic instructions.

“Given the logistical complexities and costs associated with ex vivo CAR-T cell manufacturing, in vivo generation of CAR-T cells has the potential to make these therapies safer and more accessible,” the researchers noted.

Simplified nanoparticle design

The newly developed nanoparticles are composed of poly(beta-amino ester) (PBAE) polymers that biodegrade after delivering their cargo. The nanoparticles encapsulate mRNA encoding an anti-CD19 CAR and are decorated with anti-CD3 and anti-CD28 antibodies, which help them locate and activate T cells.

Compared with many lipid nanoparticle (LNP) delivery systems that contain four or five components, the polymeric nanoparticles require only three elements: the PBAE polymer, a PEG lipid, and the mRNA payload. The simpler design may offer advantages in manufacturing and storage, as the nanoparticles can be frozen or lyophilized for long-term stability.

Promising preclinical results

In mouse studies, a single injection of the nanoparticles produced rapid immune cell reprogramming. Within 24 hours, researchers observed approximately 95% depletion of circulating B cells, while about 50% of B cells in the spleen were eliminated.

After one week, B-cell levels in the bloodstream recovered to roughly 50% of their original levels, indicating the effect was potent but partially reversible.

The results suggest the nanoparticle platform can efficiently deliver CAR-encoding mRNA to T cells in vivo, enabling them to recognize and destroy disease-causing B cells.

Overcoming a major delivery challenge

Engineering T cells directly inside the body has historically been difficult because these immune cells resist uptake of foreign materials and often degrade therapeutic cargo before it can function.

To address this, the researchers designed the nanoparticles to operate in stages—similar to rockets delivering payloads. The particles first locate and bind T cells, stimulate their activation, enter the cells, and then degrade to release the mRNA payload.

Previous work by the team showed that roughly 10% of these nanoparticles escape cellular degradation pathways, significantly higher than the 1–2% escape rate observed with many conventional nanoparticles.

Future directions

The research builds on five years of collaboration between Jordan Green and immunology expert Jonathan Schneck, M.D., Ph.D., combining advances in polymer nanoparticle engineering with immune cell activation technologies.

Researchers are now working to refine the system, improve targeting to disease-specific B cells, and better control the level of T-cell stimulation.

If further developed successfully, the polymeric nanoparticle platform could enable scalable, off-the-shelf therapies capable of generating CAR-T cells inside patients—potentially expanding access to treatments for autoimmune diseases and B-cell cancers.