Engineering a nano-drug delivery system to regulate m6A modification and enhance immunotherapy in gastric cancer.

Cancer cell membrane-derived nanoparticle drug delivery system enables precise drug delivery to tumor tissues and is a new effective way to treat solid tumors. The aim of this study is to develop a safe and effective cancer cell membrane-derived nano-delivery system targeting gastric cancer. We previously reported that EPH receptor A2 (EphA2) is an important target for gastric cancer. RNA m6A methyltransferases METTL3 is upregulated in multiple cancers and promotes cancer development by increasing the expression of multiple oncogenes. We design a new nano-delivery system PLGA-STM-TAT: nanoparticles PLGA (poly lactic acid-hydroxyacetic acid) loaded with METTL3 inhibitor STM2457 and cell-penetrating peptide TAT, and then covered with gastric cancer cell membranes equipped with YSA peptides by means of click chemistry, which targeting EphA2. The nanoparticles are specifically enriched in gastric cancer tissues, significantly increased drug accumulation, and inhibited cancer cell proliferation by decreasing key oncogenes c-MYC and BRD4. During drug administration, we found that the expression of the immune checkpoint molecule PD-L1 was suppressed, and the anti-tumor immune effect was enhanced by the nano-delivery system in combination with anti-PD1. This cancer cell membrane-derived nano-delivery system provides a new biological strategy to treat gastric cancer through effective m6A modulation and EphA2 targeting. STATEMENT OF SIGNIFICANCE: M6A modifications have important biological roles, especially in tumors. Targeting highly modified m6A in gastric cancer becomes a challenge. We developed a nano-drug delivery system for modulating m6A that could produce an effective anti-cancer therapeutic effect and that the nanoparticles enhanced antitumor immunity when combined with anti-PD1.This cancer cell membrane-derived new nano-drug delivery system shows great promise as an antitumor approach by modulating m6A modification and targeting EphA2 in gastric cancers.