Ionizable Lipid Nanoparticle-Mediated TRAIL mRNA Delivery in the Tumor Microenvironment to Inhibit Colon Cancer Progression

Abstract

Introduction

Immunotherapy has revolutionized cancer treatment by harnessing the immune system to enhance antitumor responses while minimizing off-target effects. Among the promising cancer-specific therapies, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted significant attention.

Methods

Here, we developed an ionizable lipid nanoparticle (LNP) platform to deliver TRAIL mRNA (LNP-TRAIL) directly to the tumor microenvironment (TME) to induce tumor cell death. Our LNP-TRAIL was formulated via microfluidic mixing and the induction of tumor cell death was assessed in vitro. Next, we investigated the ability of LNP-TRAIL to inhibit colon cancer progression in vivo in combination with a TME normalization approach using Losartan (Los) or angiotensin 1–7 (Ang(1–7)) to reduce vascular compression and deposition of extracellular matrix in mice.

Results

Our results demonstrated that LNP-TRAIL induced tumor cell death in vitro and effectively inhibited colon cancer progression in vivo, particularly when combined with TME normalization induced by treatment Los or Ang(1–7). In addition, potent tumor cell death as well as enhanced apoptosis and necrosis was found in the tumor tissue of a group treated with LNP-TRAIL combined with TME normalization.

Discussion

Together, our data demonstrate the potential of the LNP to deliver TRAIL mRNA to the TME and to induce tumor cell death, especially when combined with TME normalization. Therefore, these findings provide important insights for the development of novel therapeutic strategies for the immunotherapy of solid tumors.

Keywords:

• immunotherapy
• TRAIL
• mRNA
• lipid nanoparticle
• losartan
• angiotensin (1–7)

Acknowledgment

This work was funded by National Council for Scientific and Technological Development-CNPq (401390/2020-9; 442731/2020-5; 305932/2022-5; 422002/2023- 830 2; 408482/2022-2), PRPq-UFMG, CAPES (88887.506690/2020-00; 38/2022 Programa de desenvolvimento da pós-graduação parcerias estratégicas nos estados III), and FAPEMIG (APQ-00826-21; APQ-02402-23; RED-00202-22 Rede de Pesquisa em Imunobiológicos e Biofármacos para terapias avançadas e inovadoras). P.P.G.G. is supported by CNPq (442731/2020-5; 305932/2022-5; 422002/2023-2; 408482/2022-2),FAPEMIG (APQ-00826-21; APQ-02402-23), and MCTI/FINEP—MS/SCTIE/DGITIS/CGITS (6205283B-BB28-4F9C-AA65-808FE4450542). The authors thank the Network Technological Platforms from FIOCRUZ, for the support and financing of the services provided by the Microscopy and Image Microanalysis Platform - René Rachou Institute/Fiocruz Minas.

Disclosure

The authors declare that they have no conflicts of interest in this work.