Researchers at Xiamen University and collaborating institutions developed a polymer–lipid nanoparticle that delivers messenger RNA and activates T cells directly inside the body without antibody tags, according to a study published in Nature Materials. The delivery carrier generates chimeric antigen receptor (CAR) T cells in situ to target diseased tissue.
Conventional lipid nanoparticles often require conjugated targeting antibodies to locate specific immune cells and require external stimulants to induce activation. The new vehicle, designated ERTLNPs, uses p-toluenesulfonyl arginine-modified oligoethylenimine-based lipid formulations. Following systemic administration in animal trials, ERTLNPs preferentially delivered mRNA payloads to T cells within the spleen, entering primary T cells through macropinocytosis.
The nanoparticles intrinsically activate T cells without exogenous stimulation by engaging the PI3K/AKT/mTOR signalling axis. This metabolic reprogramming occurs through dual pathways: cell-surface interaction with insulin-like growth factor 1 receptor (IGF-1R) and lysosomal arginine sensing via TM4SF5. The resulting downstream signaling promoted T cell expansion and restrained exhaustion markers during mRNA expression.
To test therapeutic function, researchers administered ERTLNPs loaded with mRNA encoding a fibroblast activation protein (FAP) CAR. Systemic delivery generated functional CAR T cells in situ, which eliminated pathological fibroblasts in mouse models of liver fibrosis and inhibited tumor growth in orthotopic pancreatic cancer models with minimal off-target effects.
Peer reviewers for the work included Mohamed Abou-el-Enein, Michael Mitchell, and Marshall Padilla. The study authors deposited corresponding RNA-sequencing data in the Sequence Read Archive under accession code PRJNA1477236.
