# DNA‐Loaded Nanoparticles Reprogram the Tumor Immune Microenvironment to Treat Brain Tumors

## TL;DR

This paper shows how DNA-loaded nanoparticles can reprogram brain tumor cells to boost immune responses, leading to tumor regression and long-term survival in animal models.

## Contribution

A novel antigen-agnostic nanoparticle platform is introduced for reprogramming brain tumor cells into antigen-presenting cells using immunostimulatory genes.

## Key findings

- DNA-loaded nanoparticles induce tumor cell overexpression of 4-1BBL and IL-12, transforming them into antigen-presenting cells.
- The treatment results in reduced tumor growth and complete regression in both meningioma and glioblastoma models.
- The approach activates cytotoxic T-cells and enhances immune infiltration without requiring viral vectors or ex vivo manufacturing.

## Abstract

Despite advances in treatment and therapeutic strategies, patients with brain tumors, including glioblastoma (GBM) and meningioma, still face high rates of recurrence, morbidity, and mortality. Nonviral biodegradable nanoparticles are advanced materials with the potential to reprogram brain tumor cells and the tumor immune microenvironment. Localized delivery of poly(beta‐amino ester) nanoparticles encapsulating immunostimulatory genes is utilized to reprogram brain tumor cells into tumor‐associated antigen‐presenting cells (tAPCs) by inducing overexpression of costimulatory 4‐1BBL on the surface of brain tumor cells and IL‐12 secreted into the tumor microenvironment. In both a humanized mouse model using human meningioma (IOMM‐Lee) and an immunocompetent syngeneic orthotopic model using mouse GBM (CT‐2A), delivery of 4‐1BBL/IL‐12 DNA‐loaded nanoparticles results in reduced tumor growth, as well as complete tumor regression and long‐term survival in some animals. The 4‐1BBL/IL‐12 gene delivery platform is an antigen‐agnostic, off‐the‐shelf biotechnology that can successfully activate cytotoxic T‐cells in tumors, improve tumor infiltration by immune cells, and enhance antitumor responses to otherwise refractory brain tumors. This nanoparticle reprogramming approach can lead to safe, long‐lasting endogenous cellular immune responses that specifically target multiple types of brain tumors that exhibit antigen heterogeneity in a patient‐accessible manner without using viruses or ex vivo cellular manufacturing.

Biodegradable poly(beta‐amino ester) nanoparticles can be employed to deliver immunostimulatory genes (4‐1BBL and IL‐12) to reprogram brain tumor cells into antigen‐presenting cells to stimulate an anti‐tumor response, resulting in tumor regression and long‐term survival in GBM and meningioma models. This platform represents an antigen‐agnostic strategy that can lead to a clinically accessible platform for personalized immunotherapy in brain cancer.© 2025 WILEY‐VCH GmbH