Macrophage Reprogramming via the Modulation of Unfolded Protein Response with siRNA-Loaded Magnetic Nanoparticles in a TAM-like Experimental Model

Abstract

New therapeutic strategies are required in cancer therapy. Considering the prominent role of tumor-associated macrophages (TAMs) in the development and progression of cancer, the re-education of TAMs in the tumor microenvironment (TME) could represent a potential approach for cancer immunotherapy. TAMs display an irregular unfolded protein response (UPR) in their endoplasmic reticulum (ER) to endure environmental stress and ensure anti-cancer immunity. Therefore, nanotechnology could be an attractive tool to modulate the UPR in TAMs, providing an alternative strategy for TAM-targeted repolarization therapy. Herein, we developed and tested polydopamine-coupled magnetite nanoparticles (PDA-MNPs) functionalized with small interfering RNAs (siRNA) to downregulate the protein kinase R (PKR)-like ER kinase (PERK) expression in TAM-like macrophages derived from murine peritoneal exudate (PEMs). After the evaluation of the cytocompatibility, the cellular uptake, and the gene silencing efficiency of PDA-MNPs/siPERK in PEMs, we analyzed their ability to re-polarize in vitro these macrophages from M2 to the M1 inflammatory anti-tumor phenotype. Our results indicate that PDA-MNPs, with their magnetic and immunomodulator features, are cytocompatible and able to re-educate TAMs toward the M1 phenotype by PERK inhibition, a UPR effector contributing to TAM metabolic adaptation. These findings can provide a novel strategy for the development of new tumor immunotherapies in vivo.

mAb-Functionalized Biomimetic MamC-Mediated-Magnetoliposomes as Drug Delivery Systems for Cancer Therapy

“…Iron content within cells was measured as described previously [ 58 ]. Briefly, cells (≈50 × 10 4 and 25 × 10 4 for GTL-16 and Huh7, respectively) were seeded in 6-well plates and incubated as reported above.…”

Reprogramming Tumor-Associated Macrophage Using Nanocarriers: New Perspectives to Halt Cancer Progression

“…Suppression of PERK resulted in downregulation of other downstream effectors of the PERK pathway, contributing to UPR (ATF4 and CHOP), and a decrease in level of M2 markers (in particular CD206) and an increase in M1 markers (CD86 and inflammatory cytokines). Therefore, authors concluded that modulation of UPR resulted in reprogramming of M2 to M1 [113].…”