Nanoparticles Hitchhike on Monocytes for Glioblastoma Treatment after Low-Dose Radiotherapy

Glioblastomas (GBMs) are aggressive primary brain tumorswith fataloutcome. Traditional chemo-radiotherapy has poor therapeutic effectand significant side effects, due to the drug and radiotherapy (RT)resistance, natural blood-brain barrier, and high-dose RT damage.Even more, tumor-associated monocytes (macrophages and microglia,TAMs) constitute up to 30%-50% of the GBM cellular content,and the tumor microenvironment (TME) in GBM is extremely immunosuppressive.Here, we synthesized nanoparticles (D@MLL) that hitchhike on circulatingmonocytes to target intracranial GBMs with the assistance of low-doseRT. The chemical construction of D@MLL was DOX & BULL;HCl loaded MMP-2peptide-liposome, which could target monocytes by the surface modifiedlipoteichoic acid. First, low-dose RT at the tumor site increasesmonocyte chemotaxis and induces M1 type polarization of TAMs. Subsequently,the intravenous injected D@MLL targets circulating monocytes and hitchhikeswith them to the central site of the GBM area. DOX & BULL;HCl was thenreleased by the MMP-2 response, inducing immunogenic cell death, releasingcalreticulin and high-mobility group box 1. This further contributedto TAMs M1-type polarization, dendritic cell maturation, and T cellactivation. This study demonstrates the therapeutic advantages ofD@MLL delivered by endogenous monocytes to GBM sites after low-doseRT, and it provides a high-precision treatment for GBMs.