Genetically Engineered IL12/CSF1R-Macrophage Membrane-Liposome Hybrid Nanovesicles for NIR-II Fluorescence Imaging-Guided and Membrane-Targeted Mild Photothermal-Immunotherapy of Glioblastoma.

It is a big challenge for precision therapy of glioblastoma, mainly due to the existence of blood-brain barrier (BBB), tumor immunosuppressive microenvironment (TIM), and lack of efficient treatment paradigms. Herein, a theranostic nanoplatform for the second near-infrared window (NIR-II) fluorescence imaging-guided membrane-targeted mild photothermal-immunotherapy of glioblastoma using genetically engineered CSF1R/IL12-macrophage membrane (MM)-liposome hybrid nanovesicles, is reported. By mimicking lipophilic membrane probe (Dil) with octadecyl chains, a NIR-II emissive photothermal dye (IRC18), which realizes labeling of nanovesicle lipid bilayers for biodistribution tracing, glioblastoma diagnosis, and molecular imaging of tumoral microenvironment, is synthesized. Importantly, MM and c-RGD-decorated liposome together offer BBB crossing, tumor targeting, and long-term circulation; while, the genetically overexpressed CSF1R and IL12 on MM surface contribute to effective modulation of M2-to-M1 macrophage repolarization and local promotion of T cell cytotoxicity in glioblastoma microenvironment, respectively. Notably, through membrane fusion, IRC18 dyes translocate from nanovesicle lipid bilayers to glioblastoma membranes, which achieve membrane-targeted mild photothermal therapy to ablate primary tumor and induce immunogenic cell death to promote antigen presentation. More importantly, the combined blockade of the CSF1-CSF1R axis and IL-12 enrichment not only reprograms the tumor microenvironment through macrophage M1 repolarization but also activates cytotoxic T cells, ultimately achieving complete glioblastoma eradication. This research provides an efficient theranostic paradigm for glioblastoma treatment.