Intranasal nano-immunotherapy for glioma: bypassing the blood–brain barrier, reprogramming the immune microenvironment, and bridging preclinical validation
- 1Department of Anesthesiology, Second Affiliated Hospital of Dalian Medical University
- 2Liaoning Laboratory of Cancer Genomics and Epigenomics, College of Basic Medical Sciences, Dalian Medical University
Abstract
Glioma, particularly glioblastoma, remains difficult to treat because of limited drug penetration across the blood–brain barrier, profound immune suppression, and insufficient intracranial exposure of systemic immunotherapies. Intranasal nano-immunotherapy is being explored as a potential strategy that may integrate noninvasive nose-to-brain delivery with nanocarrier-mediated immune reprogramming. Intranasal administration may partially bypass conventional vascular barriers through olfactory, trigeminal, mucosal, cerebrospinal-fluid, and perivascular transport routes, while nanoparticles are designed to protect immune-active payloads, support brain tumor targeting, and enable controlled release. Current evidence spans three distinct levels: direct intranasal glioma nano-immunotherapy, intranasal glioma nanodelivery without demonstrated immune reprogramming, and non-intranasal glioma nano-immunotherapy that provides mechanistic support for future intranasal adaptation. Across these evidence levels, investigated platforms include peptide-guided nanomicelles, lipid nanoparticles, biomimetic nanoparticles, ferritin-based nanovectors, spherical nucleic acids, extracellular vesicles, bacterial outer membrane vesicles, and stimuli-responsive systems. These platforms can deliver immune-activating cargos, such as STING or TLR agonists; gene-regulatory cargos, such as siRNA and CRISPR-Cas9 components; and microenvironment-modulating cargos, such as chemokine-axis inhibitors, checkpoint-modulating agents, and combination payloads. Through these payloads, intranasal nanoplatforms may activate innate immune sensing, reverse myeloid-mediated suppression, enhance T-cell infiltration, and induce immunogenic cell death. However, translation remains limited by dosing uncertainty, species differences in nasal anatomy, mucosal and neurological safety concerns, manufacturing complexity, and incomplete immune pharmacodynamic validation. This review summarizes recent advances in intranasal and brain-targeted glioma nano-immunotherapy, highlights key immune mechanisms, and proposes a preclinical validation framework for evaluating whether experimental efficacy can be advanced toward clinically testable treatment designs.
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BibTeX
@article{li2026intranasal,
title = {{Intranasal nano-immunotherapy for glioma: bypassing the blood–brain barrier, reprogramming the immune microenvironment, and bridging preclinical validation}},
author = {Leina Li and Moli Wu and Liya Li},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1950362},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1950362/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Intranasal nano-immunotherapy for glioma: bypassing the blood–brain barrier, reprogramming the immune microenvironment, and bridging preclinical validation
AU - Leina Li
AU - Moli Wu
AU - Liya Li
PY - 2026
DA - 2026/10/20
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1950362
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1950362/full
AB - Glioma, particularly glioblastoma, remains difficult to treat because of limited drug penetration across the blood–brain barrier, profound immune suppression, and insufficient intracranial exposure of systemic immunotherapies. Intranasal nano-immunotherapy is being explored as a potential strategy that may integrate noninvasive nose-to-brain delivery with nanocarrier-mediated immune reprogramming. Intranasal administration may partially bypass conventional vascular barriers through olfactory, trigeminal, mucosal, cerebrospinal-fluid, and perivascular transport routes, while nanoparticles are designed to protect immune-active payloads, support brain tumor targeting, and enable controlled release. Current evidence spans three distinct levels: direct intranasal glioma nano-immunotherapy, intranasal glioma nanodelivery without demonstrated immune reprogramming, and non-intranasal glioma nano-immunotherapy that provides mechanistic support for future intranasal adaptation. Across these evidence levels, investigated platforms include peptide-guided nanomicelles, lipid nanoparticles, biomimetic nanoparticles, ferritin-based nanovectors, spherical nucleic acids, extracellular vesicles, bacterial outer membrane vesicles, and stimuli-responsive systems. These platforms can deliver immune-activating cargos, such as STING or TLR agonists; gene-regulatory cargos, such as siRNA and CRISPR-Cas9 components; and microenvironment-modulating cargos, such as chemokine-axis inhibitors, checkpoint-modulating agents, and combination payloads. Through these payloads, intranasal nanoplatforms may activate innate immune sensing, reverse myeloid-mediated suppression, enhance T-cell infiltration, and induce immunogenic cell death. However, translation remains limited by dosing uncertainty, species differences in nasal anatomy, mucosal and neurological safety concerns, manufacturing complexity, and incomplete immune pharmacodynamic validation. This review summarizes recent advances in intranasal and brain-targeted glioma nano-immunotherapy, highlights key immune mechanisms, and proposes a preclinical validation framework for evaluating whether experimental efficacy can be advanced toward clinically testable treatment designs.
SN - 1664-3224
ER -