Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response.

ABSTRACT

PURPOSE: Some chemotherapeutics have been shown to induce both the release of damage-associated molecular patterns (DAMPs) and the production of type I interferon (IFN-I), leading to immunogenic cell death (ICD). However, the standard chemotherapy drug for glioma, temozolomide (TMZ), cannot induce ICD as it cannot activate IFN-I signaling. Moreover, inefficient delivery of immunostimulants across the blood-brain barrier (BBB) is the main obstacle to overcome in order to induce local immune responses in the brain. METHODS: A new oligonucleotide nanoformulation (Au@PP)/poly(IC)) was constructed by coating gold nanoparticles (AuNPs) with methoxypolyethylene glycol (mPEG)-detachable (d)-polyethyleneimine (PEI) (Au@PP) followed by inducing the formation of electrostatic interactions with polyinosinic-polycytidylic acid (poly(IC)). Intracranial GL261 tumor-bearing C57BL/6 mice were used to explore the therapeutic outcomes of Au@PP/poly(IC) plus TMZ in vivo. The anti-tumor immune response in the brain induced by this treatment was analyzed by RNA sequencing and immunohistochemical analyses. RESULTS: Au@PP/poly(IC) induced IFN-I production after endocytosis into glioma cells in vitro. Additionally, Au@PP/poly(IC) was efficiently accumulated in the glioma tissue after intranasal administration, which allowed the nanoformulation to enter the brain while bypassing the BBB. Furthermore, Au@PP/poly(IC) plus TMZ significantly improved the overall survival of the tumor-bearing mice compared with group TMZ only. RNA sequencing and immunohistochemical analyses revealed efficient immune response activation and T lymphocyte infiltration in the Au@PP/poly(IC) plus TMZ group. CONCLUSION: This study demonstrates that intranasal administration of Au@PP/poly(IC) combined with TMZ induces ICD, thereby stimulating an in situ immune response to inhibit glioma growth.