Manganese-tannic acid immunomodulators potentiate PDGFRβ CAR-T cell function for additive therapy against liver fibrosis.

Chimeric antigen receptor (CAR)-T cell therapy has achieved considerable success in treating malignant tumors. However, its therapeutic efficacy in hepatic fibrosis remains unclear. The activated hepatic stellate cells (aHSCs) represent a central driver in the initiation and progression of liver fibrosis. During this activation process, the expression of platelet-derived growth factor receptors β (PDGFRβ) is significantly upregulated, indicating that PDGFRβ may represent a promising therapeutic target for specifically targeting aHSCs. Based on this rationale, we design a CAR-T cell that targets PDGFRβ for the specific elimination of aHSCs. To potentiate the efficacy of PDGFRβ CAR-T cells, we develop manganese-tannic acid (MT) nanoparticle immunomodulators with a uniform particle size and excellent T1-weighted magnetic resonance imaging (MRI) performance, capable of anchoring to the surface of PDGFRβ CAR-T cells and effectively remodeling the hepatic fibrotic microenvironment. In vivo PDGFRβ CAR-T cell therapy enhanced with MT nanoparticles additively improved anti-fibrotic treatment outcomes. Furthermore, we discover a novel mechanism by which MT nanoparticles enhance the proliferation, and thus the cytotoxicity of PDGFRβ CAR-T cells by upregulating the activity of the RAS signaling pathway. Overall, our well-designed MT nanoparticle-modified PDGFRβ CAR-T cell immunotherapy strategy demonstrates excellent anti-fibrotic effects, providing a promising therapeutic regimen for hepatic fibrosis.