Researchers have engineered synthetic microparticles that sustain the expansion of human chimeric antigen receptor T cells for more than 100 days outside the body, according to a study published in Nature Communications.
The platform, designated CAREp, consists of programmable DNA-scaffolded PLGA microparticles displaying CAR-targeting antigens and CD28-costimulatory antibodies. Designed to repeatedly stimulate human CD8+ CAR-T cells ex vivo, the particles sustained the growth of a-EGFR CAR-T cells across both 4-1BBζ and CD28ζ constructs. The approach achieved up to 1018-fold cumulative expansion, surpassing benchmark stimulation methods using tumor cells or CD3/CD28-Dynabeads without requiring genetic rewiring.
T cells cultured with the particles maintained effector function and mitochondrial fitness throughout the expansion period. The cells demonstrated clonal enrichment, delayed exhaustion, and initially preserved memory-associated progenitor states. The stimulation also transiently activated telomerase, which delayed telomere attrition.
Early transcriptomic profiling revealed coordinated activation of DNA repair, chromatin remodeling, telomere maintenance, and mitochondrial function. At the same time, the particles restricted signaling programs tied to cell differentiation. The authors reported that nanoscale ligand organization synchronizes acute CAR-T signaling with durable proliferative and metabolic states.
Investigators from Drexel University and the University of California, San Francisco led the research alongside collaborators at Stanford University, the University of Pennsylvania, Thomas Jefferson University, and Brown University. The work received support from National Institutes of Health Grant 1U54CA244438, the Coulter-Drexel Translational Research Partnership Program, the Margaret Q. Landenberger Research Foundation, and the Drexel University Startup Fund. Several study authors, including Xiao Huang, Tejal A. Desai, Wendell A. Lim, and Jasper Z. Williams, are inventors on pending patents covering the technology.
