Triple-remodeling of tumor microenvironment through hyaluronidase-assisted folate-targeted lipid nanoparticle-mediated siVEGF/siPD-L1 for enhanced tumor immunotherapy

Abstract

Background: In tumor therapy, traditional single-treatment methods often fail to achieve ideal results because of problems like the complex tumor microenvironment, immune escape mechanisms, and abnormal blood vessel formation. Although there are now several combined treatment strategies, challenges remain in precise drug delivery and achieving multi - target synergistic effects. Methods: This study aims to create an efficient combined anti-tumor lipid nanoparticle (LNP) delivery system. We added DMG-PEG2000-FA to the four-component lipid nanoparticle system and used microfluidic technology to prepare FA-LNP with tumor-targeting groups. These delivery systems were loaded with the pSpam-1 gene, siVEGF, and siPD-L1 separately. Results: The pSpam-1 gene can express hyaluronidase in tumor tissues, degrade the tumor extracellular matrix, and boost the infiltration of nanodrugs and immune cells into tumor tissues. siVEGF exerts an anti-angiogenic effect, cutting off tumor nutrient supply. siPD-L1 achieves immune checkpoint blockade, activating the body’s immune system. Experimental show that this FA-LNP achieves effective multi-target synergy, greatly inhibiting tumor growth and achieving highly efficient combined anti-tumor effects both in vitro and in vivo. Further immune mechanism research reveals it can regulate immune cell function and distribution in the tumor microenvironment. Conclusions: Combining extracellular matrix degradation, anti-angiogenesis, and immune checkpoint blockade led to a highly efficient synergistic anti-tumor effect. The in-depth immune mechanism research offers valuable insights into how these strategies interact and contribute to the overall anti-tumor response. This FA-LNP delivery system is expected to offer a safer and more effective tumor therapy strategy and promote personalized tumor treatment development.