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Programmable microparticles rewire CAR signaling to enable super-physiological expansion of human T cells in vitro
Conference proceeding   Open access

Programmable microparticles rewire CAR signaling to enable super-physiological expansion of human T cells in vitro

Qinghe Zeng, Landon John Flemming, Wendell Lim, Qizhi Tang, Tejal Desai and Xiao Huang
bioRxiv (Cold Spring Harbor Laboratory)
2026
DOI: https://doi.org/10.1101/2025.07.17.665438
url
https://doi.org/10.1101/2025.07.17.665438 View
Preprint (Author's original) Open Open Access (License Unspecified)

Abstract

T cell proliferative capacity and persistence critically determine the therapeutic success of chimeric antigen receptor (CAR) T cells. However, it remains unknown if and how human CAR-T cells can be externally programmed to reach maximal proliferative capacity. Here, we use programmable PLGA microparticles functionalized with CAR-antigens and CD28-costimulatory antibodies (CAREp) to repeatedly stimulate human CD8+ CAR-T cells in vitro. CAREp-stimulated CAR-T cells expanded continuously for over 100 days—versus ∼30 days with tumor cell stimulation—and achieved up to 1018-fold cumulative expansion, greatly surpassing CD3/28-Dynabeads. Early-phase transcriptomic responses— upregulation of DNA repair, cell cycle, telomere maintenance, and mitochondrial pathways—aligned with long-term outcomes: massive proliferation, telomere stability, robust respiration, and preserved progenitor phenotype by single-cell sequencing. Differentiation and exhaustion signals were broadly suppressed. Transient telomerase activity further supported physiologic expansion. These findings demonstrate that nanoscale-controlled extracellular cues can rewire intracellular signaling to drive durable, super-physiological expansion of functional CAR-T cells.

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