Intranasal hybrid vesicles delivering personalized in situ nano-vaccines induce glioblastoma remodeling to sensitize immunotherapy

Abstract

Personalized in situ tumor vaccine (PISTV), an attractive type of cancer immunotherapy, promotes a potent T cell anti-cancer immune response in multiple malignancies. Nevertheless, the limited cancer elimination efficacy of PISTV was exhibited in glioblastoma (GBM). Herein, an intranasal hybrid vesicle is designed based on ginseng-derived nanoparticles (GDNPs) fusing with liposomes, encapsulating shikosin (SKN), muscone, and MAN-CpG ODN (mCpG) to enable personalized in situ tumor vaccination for amplifying anti-GBM immune response. Following intranasal administration, the hybrid vesicles penetrated the nasal mucosal barrier and circumvented the blood-brain-barrier via the olfactory bulbar pathway. Subsequently, these nano-vaccines reached the tumor site, attributed to ginsenoside Rg3 in GDNPs. SKN-mediated whole tumor cell lysis served as a tumor-antigen pool to combine with immune adjuvant mCpG, resulting in the personalized in situ tumor vaccination, then recruiting dendritic cells (DCs) and promoting DCs maturation. Afterwards, DCs antigen presentation was enhanced to mobilize T cells, differentiating into cytotoxic T lymphocytes, thus inducing adaptive anti-tumor immunity. Furthermore, the GDNPs-mediated tumor-associated macrophages repolarization combines with SKN-blocked glycolytic pathway to reverse the immunosuppressive TME from “cold” into “hot”, thereby inducing innate immunity. We developed a nanoplatform that can deliver immunogenic cell death activators and Toll-like receptor agonists to antigen-capturing cells, synchronously conveying glycolysis inhibitors and TAM repolarization inducers to TME. This work demonstrated its robust capacity to activate innate and adaptive immune responses in distal metastasis, rechallenge, and humanized patient-derived xenograft tumor-bearing mice, providing a promising pathway for immunotherapeutic sensitization of GBM.