Engineering an AIEgen-based platform integrating CRISPR/Cas9 to remodel the tumor microenvironment and reinforce photo-immunotherapy against glioblastom.

Glioblastoma remains one of the most lethal brain tumors. Although immunotherapy and other therapeutic modalities has achieved significant therapeutic success in several malignancies, its efficacy in glioblastoma remains limited primarily due to the complex tumor microenvironment (TME) and physiological barriers such as the blood-brain barrier (BBB). In this context, nanomedicine and gene editing have emerged as promising strategies due to their unique ability to cross the BBB and protect therapeutic agents through intrinsic physicochemical properties. To overcome the physiological barriers for better therapeutic outcomes. Here, a novel aggregation-induced emission luminogen (AIEgen), NDA-DPE, was synthesized, exhibiting NIR-I to NIR-II fluorescence and dual photothermal (PTT) and photodynamic (PDT) properties through restricted intramolecular motion. Bone-derived neutrophil-based biomimetic nanoparticles (bNe@AIE/Cas9-CD73) were then prepared by integrating NDA-DPE with CRISPR/Cas9-mediated CD73 gene silencing. The neutrophil encapsulation enabled efficient BBB penetration and targeted accumulation in glioblastoma tissue. CRISPR/Cas9-CD73 downregulated CD73 expression, disrupted the ATP-adenosine axis, and reshped the immunosuppressive TME into an immuno-supportive one, increasing the therapeutic sensitivity of tumor cells. Under NIR-II excitation, bNe@AIE/Cas9-CD73 achieved fluorescence-guided PTT and PDT, inducing immunogenic cell death (ICD), stimulating immune-cell recruitment, and activating systemic antitumor immunity. bNe@AIE/Cas9-CD73 demonstrated a potent gene-photothermal-photodynamic-immune synergistic effect, significantly inhibiting glioblastoma growth and establishing a promising nanoplatform for effective and targeted glioblastoma treatment.