Antitumor Activity of Anti‐miR‐21 Delivered through Lipid Nanoparticles

Abstract

The ability of lipid nanoparticles (LNPs) to deliver nucleic acids have shown a great therapeutic potential to treat a variety of diseases. Here, an optimized formulation of QTsome lipid nanoparticles (QTPlus) is utilized to deliver an anti‐miR‐21 (AM21) against cancer. The miR‐21 downstream gene regulation and antitumor activity is evaluated using mouse and human cancer cells and macrophages. The antitumor activity of QTPlus encapsulating AM21 (QTPlus‐AM21) is further evaluated in combination with erlotinib and atezolizumab (ATZ). QTPlus‐AM21 demonstrates a superior miR‐21‐dependent gene regulation and eventually inhibits A549 non‐small cell lung cancer growth in vitro. QTPlus‐AM21 further induces chemo‐sensitization of A549 cells to erlotinib with a combination index of 0.6 in inhibiting A549 cell growth. When systemically administers to MC38 tumor‐bearing mouse model, QTPlus‐AM21 exhibits an antitumor immune response with over 80% tumor growth inhibition (TGI%) and over twofold and fourfold PD‐1 and PD‐L1 upregulation in tumors and spleens. The combination therapy of QTPlus‐AM21 and ATZ further shows a higher antitumor response (TGI% over 90%) and successfully increases M1 macrophages and CD8 T cells into TME. This study provides new insights into the antitumor mechanism of AM21 and shows great promise of QTPlus‐AM21 in combination with chemotherapies and immunotherapies.

Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy

“…Recognizing the role of epigenetic changes in immune dysfunction, the delivery of miRNAs has been explored in cancer immunotherapy. Lipid nanoparticles delivering anti-miR-21 have demonstrated the ability to stimulate M1 polarization of macrophages and enhance the infiltration of CD 8+ T cells [ 298 ].…”