Biomimetic universal CAR-mesenchymal stem cell nanohybrids for anti-tumor therapy

Current autologous chimeric antigen receptor (CAR)-T cell therapies are hindered by significant challenges, including the lack of off-the-shelf availability, prolonged manufacturing timelines, and inconsistent product quality, which limit their broader application and clinical efficacy. To address these limitations, we developed an innovative universal CAR nanoplatform by engineering mesenchymal stem cells (MSCs) with CAR and integrating them with multifunctional hybrid nanoparticles. This platform leverages the intrinsic tumor-homing properties of MSCs and the specificity of CAR to achieve precise tumor targeting and eradication. Specifically, we targeted C-type lectin-like molecule-1 (CLL-1), a marker specifically expressed on acute myeloid leukemia (AML) blast cells and leukemia stem cells (LSCs), to create an anti-CLL-1 CAR-MSC (aCLL-1 CAR-MSC) nanoplatform for AML therapy. To further enhance therapeutic efficacy, we incorporated biomimetic nanotechnology for the targeted delivery of shikonin (SK) nanohybrids, which amplify SK-induced immunogenic cell death in tumor. This dual approach not only improved anti-AML activity but also extended the in vivo circulation time of the nanodrug. In both AML orthotopic and subcutaneous tumor models, the camouflaged nano-system remarkably suppressed leukemia growth and enhanced immune responses. Notably, it achieved a high tumor inhibition rate of 92.7% and effectively induced the polarization of macrophages towards the tumor-fighting M1 phenotype. Collectively, it is the first nanoplatform designed to synergize chemotherapy and immunotherapy via targeting CLL-1, a unique leukemia antigen, offering a robust foundation for its potential clinical translation in the treatment of AML and other malignancies.