Johns Hopkins Develops Simplified Nanoparticles for In-Body CAR-T Cell Engineering
核心洞察
Johns Hopkins researchers have developed biodegradable nanoparticles (搜索) that can engineer immune T cells (搜索) directly within the body, eliminating the need for costly and time-consuming external cell manipulation required in current CAR-T therapies.
The simplified three-component nanoparticles (搜索) successfully depleted 95% of target B cells (搜索) in mouse blood within 24 hours using a single dose, demonstrating potential for treating blood cancers (搜索) and autoimmune diseases like lupus (搜索).
This off-the-shelf approach could make engineered immune cell therapy more scalable and accessible compared to existing CAR-T treatments, with researchers securing over $40 million in federal funding to advance development.
Johns Hopkins Medicine (搜索) scientists have developed a simplified version of biodegradable nanoparticles (搜索) that can "educate" the immune system to find and destroy disease-causing cells throughout the body, potentially revolutionizing the field of engineered immune cell therapy. The breakthrough, published March 11 in Science Advances, offers a more efficient and cost-effective alternative to current CAR-T cell treatments.
Addressing CAR-T Therapy Limitations
Current CAR-T cell therapy has shown success in treating blood cancers (搜索) by removing immune T cells (搜索) from patients' blood and engineering them in laboratories to recognize and kill cancer cells. However, this process of removing blood cells and individually engineering them outside the body is costly and inefficient, according to the researchers.
"These experiments were successful using just one dose of the nanoparticles (搜索), and an advantage of using an off-the-shelf therapy is the potential for scalable manufacture and broad accessibility, whereas current forms of CAR-T therapies are very expensive and time-consuming," said Jordan Green, Ph.D., the Herschel L. Seder Professor of Biomedical Engineering at Johns Hopkins University School of Medicine.
Innovative Nanoparticle Design
The Johns Hopkins nanoparticles (搜索) are composed of polymers - strings of molecules called ester units that biodegrade in water. The nanoparticle surface features two major components: antiCD3 and antiCD28 antibody molecules that help the nanoparticles find and stimulate T cells (搜索). This represents a more streamlined design compared to lipid-based nanoparticles developed by other researchers, which require five components versus the Johns Hopkins version's three components.
The nanoparticles (搜索) carry mRNA (搜索) cargo - genetic material that instructs T cells (搜索) to express receptors on their surface that detect cancer and lupus (搜索)-causing B cells (搜索). These engineered T cells then seek out and destroy B cells, which are the source of diseases such as lupus and blood cancers (搜索) including leukemia (搜索) and lymphoma (搜索).
Promising Preclinical Results
In the current study involving healthy mice, the nanoparticles (搜索) demonstrated remarkable efficacy. Within 24 hours of injection, 95% of target B cells (搜索) were depleted in circulating blood, and approximately 50% of B cells were destroyed in the spleen across all test subjects. After one week, B cells in the blood returned to about 50% of their original quantity, suggesting controlled and temporary immune modulation.
Overcoming Technical Challenges
Developing nanoparticles (搜索) capable of reaching T cells (搜索) throughout the blood and organs presented significant challenges. "Designing nanoparticles that can reach T cells throughout the blood and organs is more difficult than delivering them directly to a localized site, such as the eye," Green explained. T cells naturally resist taking up particles and often degrade and expel them, which serves as a protective mechanism against viral infections.
Green describes the nanoparticles (搜索)' function using a rocket analogy: "The nanoparticles work in a stepwise way, much like rockets traveling to outer space work in stages to lift off, engage boosters, detach them and finally deliver cargo." The nanoparticles seek out T cells (搜索), stimulate them to activate and multiply, pass through the cell wall, and then degrade to deliver their mRNA (搜索) cargo.
Superior Delivery Efficiency
The Johns Hopkins team achieved superior delivery efficiency compared to existing technologies. In previous studies, approximately 10% of their nanoparticles (搜索) successfully escaped cellular degradation compartments to deliver genetic cargo, compared to just 1-2% for other nanoparticles that are immediately degraded and ejected from cells. The current study showed that nanoparticles degrade and release their mRNA (搜索) contents within a few hours in mice.
Federal Funding and Future Development
The research team has secured significant federal support for continued development. Green, Schneck, and colleagues have been named collaborators by biotechnology company ImmunoVec (搜索) on a more than $40 million grant from the Advanced Research Projects Agency for Health (搜索) to develop these cell engineering tools.
The researchers plan to continue refining the nanoparticles (搜索), focusing on better targeting of diseased B cells (搜索) and developing the ability to modulate T-cell stimulation levels. This work represents five years of collaborative effort between Green's expertise in polymer-based nanoparticles and immunology expert Jonathan Schneck's research on artificial immune cells.