# Thermo-Magnetic Induction of Pro-Inflammatory Microglia: A Lipid-Based Nanovector Strategy for Glioblastoma Immunotherapy

## TL;DR

This paper introduces a new method using magnetic nanoparticles to activate microglia against brain tumors, showing promising results in triggering an immune response.

## Contribution

A novel lipid-based magnetic nanovector strategy is proposed to remotely activate microglia for glioblastoma immunotherapy.

## Key findings

- LMNVs induced a pro-inflammatory M1-like microglial response through magneto-thermal conversion.
- AMF-stimulated LMNVs significantly reduced the viability of glioblastoma cells via immunogenic cell death.
- Transcriptomic analysis confirmed the polarization of microglia and upregulation of inflammatory markers.

## Abstract

Microglia, the main
immune cells in the central nervous
system
(CNS), maintain physiological homeostasis and react to pathological
changes. Besides their neuroprotective function, they play a crucial
role in brain tumor microenvironments such as glioblastoma (GBM),
by composing up 40% of the tumor mass. Glioma-associated microglia
exhibit a dynamic activation state characterized mainly by an immunosuppressive
(M2-like) response, with a lesser contribution of pro-inflammatory
(M1-like) response. Modulating microglial into M1-like phenotype offers
antitumor response and a promising immunotherapy strategy against
GBM. Nanoparticles can induce microglial polarization, also modulating
pro-inflammatory responses for tumor suppression. Magnetically responsive
nanoparticles are promising nanotransducers due to their remote-control
capabilities via external magnetic fields, enabling precise therapeutic
interventions. This study proposes a novel strategy that exploits
lipid-based magnetic nanovectors (LMNVs) composed of a lipid matrix
doped with iron oxide nanoparticles to induce M1-like microglial response
through magneto-thermal conversion. Results demonstrated that LMNVs
exhibit excellent biocompatibility and efficient internalization within
human microglia (HMC3 cells). Upon alternating magnetic field (AMF)
stimulation, LMNVs triggered a sustained increase in intracellular
Ca2
+ levels, leading to the polarization of
microglia toward a pro-inflammatory M1-like phenotype. This activation
was confirmed by the upregulation of key inflammatory markers (CD40,
CD86) and cytokine release (IL-6, IL-8, and TNF-α), mirroring
the effects of IFN-γ stimulation. These findings were further
corroborated by comparative transcriptomic analysis. Notably, conditioned
medium from LMNVs + AMF-stimulated microglia significantly impaired
the viability and proliferation of both immortalized and patient-derived
GBM cells, demonstrating a potent antitumor response. The tumor cell
death was associated with immunogenic cell death (ICD), as indicated
by the translocation of the damage-associated molecular patterns,
in particular high mobility group box 1 (HMGB1) and calreticulin (CRT).
Overall, these results highlight the potential of LMNVs as a remotely
activatable nanoplatform capable of reprogramming microglia and to
promote antitumor immunity in GBM.