Journal article
Programmable CAR-engaging particles rewire human CAR T-cell signaling for sustainable ex vivo expansion
Nature communications, Forthcoming
07 Sep 2026
Featured in Collection : Drexel's Newest Publications
Abstract
T cell proliferative capacity and persistence determine the therapeutic efficacy of chimeric antigen receptor (CAR) T cells. However, strategies to externally enhance CAR-T cell expansion without genetic rewiring are lacking. Here, we engineer CAREp, programmable DNA-scaffolded PLGA microparticles displaying CAR-targeting antigens and CD28-costimulatory antibodies, to repeatedly stimulate human CD8+ CAR-T cells ex vivo. CAREp sustains a-EGFR CAR-T cell expansion for over 100 days across both 4-1BBζ and CD28ζ constructs, achieving up to 1018-fold cumulative expansion and surpassing tumor-cell or CD3/CD28-Dynabeads stimulation. Expanded cells retain effector function and mitochondrial fitness while exhibiting clonal enrichment, initially preserved memory-associated progenitor states, delayed exhaustion, and transiently activated telomerase delaying telomere attrition. Early transcriptomic responses show coordinated activation of DNA repair, chromatin remodeling, telomere maintenance, and mitochondrial function while restricting differentiation-associated signaling programs, mirroring long-term functional outcomes. These findings demonstrate that nanoscale ligand organization synchronizes acute CAR-T signaling with durable proliferative and metabolic states.
Metrics
1 Record Views
Details
- Title
- Programmable CAR-engaging particles rewire human CAR T-cell signaling for sustainable ex vivo expansion
- Creators
- Qinghe Zeng - Drexel UniversityLandon Flemming - Drexel UniversityYuanzhou Chen - University of California, San FranciscoThomas Mazumder - Parker Institute for Cancer ImmunotherapyHeinz Hammerlindl - University of California, San FranciscoGreg M. Allen - University of California, San FranciscoRicardo Almeida - University of California, San FranciscoJasper Z. Williams - University of California, San FranciscoRogelio A. Hernández-López - University of California, San FranciscoAnia-Ariadna Baetica - Drexel UniversitySara E. Meyer - Thomas Jefferson UniversityJoseph A. Fraietta - University of PennsylvaniaJustin Eyquem - University of California, San FranciscoChun J. Ye - University of California, San FranciscoWendell A. Lim - University of California, San FranciscoQizhi Tang - University of California, San FranciscoTejal A. Desai - University of California, San FranciscoXiao Huang (Corresponding Author) - University of California, San Francisco
- Publication Details
- Nature communications, Forthcoming
- Publisher
- Nature Publishing
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; Electrical and Computer Engineering; School of Biomedical Engineering and Science
- Other Identifier
- 991022207141204721