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Optimizing Lentiviral Virus-Like Particles for CAR T-Cell Engineering

Ferrara F, Wielgosz MW, Park JJ, et al. Co-Delivery of Lentiviral Vectors and Cas9-Containing Virus-Like Particles Enables Rapid, Scalable Manufacture of Gene-Edited CAR T Cells. Molecular Therapy Advances. 2026; (doi: 10.1016/j.omta.2026.201809).

Scientists believe lentiviral (LV)-based virus-like particles (VLPs) could improve chimeric antigen receptor (CAR) T-cell therapies and enable rapid, scalable production of gene-edited CAR T-cells for use "off the shelf." Inadequate T-cell expansion and persistence hinder both, and is currently addressed through gene knockout via CRISPR-Cas9-mediated gene editing. Electroporation effectively delivers Cas9 and single-guide RNA ribonucleoprotein (RNP) complexes to T cells for gene disruption but is challenged by toxicity, the potential for chromosomal abnormalities, and the high cost of equipment. A novel approach uses Cas9-containing VLPs, which lack a viral genome but deliver CRISPR components to cells as protein or mRNA. Researchers optimized the production of Cas9-RNP-containing LV VLPs in serum-free suspension culture and used them to manufacture gene-edited primary human CAR T cells. While electroporation demonstrated higher editing efficiency, VLPs resulted in recovery of twice as many cells and mediated a 10% gain in cell viability. The work demonstrates VLP production as a scalable and cost-effective alternative to electroporation for modifying CAR T cells, one that potentially accelerates access and conveys greater clinical benefit.

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