A chemokine "leverage regulation" biomimetic nanoformulation enhances CAR-T cells against solid tumors by reshaping immune cell niches.

Tumor chemokines that drives abnormal immune cell niches play a crucial role in impairing the chimeric antigen receptor (CAR)-T cell therapy against solid tumors. Here we develop a biomimetic nanoformulation with chemokine "leverage regulation" capabilities, which can establish matching migration signals to creat an immune cell niche that supports CAR-T cell therapy. The system is constructed using celecoxib (CXB)-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles and subsequently camouflaging them with mesenchymal stem cell membranes with high CXCR4 expression. Leveraging the characteristic of tumors abnormally upregulating the chemokine CXCL12 to recruit CXCR4-positive immunosuppressive cells, the biomimetic nanoformulations can achieve efficient accumulation in the tumor tissue. These nanoformulations remodel the tumor chemokine milieu by upregulating immunogenic chemokines (CXCL9, CXCL10) to selectively recruit CAR-T cells, while simultaneously serving as a nanobait to neutralize CXCL12, thereby reducing the influx of immunosuppressive cells (such as CAR-Tregs and MDSCs) to enhance the killing efficacy of CAR-T cells. This dual modulation of the chemokine network significantly improves the therapeutic efficacy of CAR-T cells against solid tumors. Our approach represents a promising strategy for advancing CAR-T cell therapy toward clinical applications for soild tumors.