Polymersome-mediated Cbl-b silencing activates T cells against solid tumors

Unleashing T cell function is critical for efficacious cancer immunotherapy. Here, we present an in vivo T cell activation strategy by silencing Casitas B-lineage lymphoma proto-oncogene b (Cbl-b), an intracellular checkpoint, to effectively combat solid tumors. The polymersomes are able to efficiently load and deliver siRNA against cblb to T cells both in vitro and in vivo, successfully silencing the cblb gene expression in primary T cells and enhancing the IL-2 receptor CD25 expression, which in turn enhances T cell function and prevents T cell exhaustion. In vitro and in vivo studies showed that siRNA against cblb caused an effective inhibition of tumor progression in subcutaneous B16-F10 and LLC models, in which a significant increase of effector T cells in peripheral blood mononuclear cells and an increase of effector T cells and a significant decrease of Treg cells in the tumor were clearly observed. This polymersome-mediated down-regulation of the cblb gene in T cells provides a promising approach for activating T cells and enhancing their anti-tumor capacity.