Immunoregulatory liposomes hitchhiking on neutrophils for enhanced carbon ion radiotherapy-assisted immunotherapy of glioblastoma

Abstract

Glioblastoma with low cure and high recurrence is a serious threat to human health. Multifaceted synergy of intensive radiotherapy (RT) and systemic chemo-immunotherapy can develop a safe and effective treatment for glioblastoma. Herein, we dope bacterial membrane (BM) into the phospholipid layer of liposome to obtain BM-doping liposome (B-Lipo), which could be further loaded with 1-methyl-D-tryptophan (1-MT) and curcumin (Cur). Utilizing the BM doping, B-Lipo/1-MT&Cur could be effectively taken up by neutrophils, and cross the blood-brain barrier to brain tumor under the stimulation of up-regulated chemokines after RT. In the RT-treated glioblastoma, BM and the loaded drugs in B-Lipo/1-MT&Cur could reinforce RT-induced positive anti-tumor immune stimulation effect, such as immunogenic cell death and T cells infiltration, and reverse RT-caused negative immune stimulation effect including the polarization of macrophages and the expression of IDO, together realizing a potent systemic innate and adaptive anti-tumor immunity. More importantly, the combination of carbon ion RT and B-Lipo/1-MT&Cur could cure most of orthotopic glioblastoma-bearing mice and prevent its recurrence without causing any physiological and neuropsychiatric damage. Therefore, glioblastoma would be completely removed by intensive RT and the ingenious combination of local and systemic therapies, promoting the development of carbon ion RT and its combination therapy.