DNA-scaffolded biomaterials enable modular and tunable control of cell-based cancer immunotherapies

Xiao Huang; Jasper Z. Williams; Ryan Chang; Zhongbo Li; Eric Gai; David M. Patterson; Yu Wei; Wendell A. Lim; Tejal A. Desai

In this work, we developed short synthetic DNA scaffolds for the efficient and versatile functionalization of proteins or antibodies on the surface of biodegradable particles (Fig. 1a) . A series of optimization studies were carried out to achieve maximum loading density, ratiometric control of moiety loading, adaptability to different particle size/composition, and feasibility for in vivo use. Micron-sized artificial immune cell engagers (AICE) were made from biocompatible poly(lactic-coglycolic acid) (PLGA) polymer 38 (Fig. 1a) . We demonstrated that: i) we can load a range of immune modulators (e.g. anti-CD3, anti-CD28, and IL-2) on AICE at controlled ratios and densities; ii) the ratiometric control of costimulatory ligands is essential for optimal ex vivo T cell activation and expansion with higher yield and less exhaustion; iii) we can locally administer antigen-presenting AICE to control ANDgate CAR-T cell activation and tumor clearance in vivo (Fig. 1a) . This modular materials-based strategy can provide versatile and precise synthetic control of natural or engineered immune cells for cancer immunotherapy 1, 12, 29 .