Cascade-responsive HA-decorated liposome/mesoporous silica nanoplatform co-delivering BMF-219 and 5-FU enhances gastric cancer chemotherapy through Menin- and p53-associated apoptotic signaling.

BACKGROUND: Our preliminary study found that Men1 is an oncogene and a potential therapeutic target in gastric cancer (GC). Chemotherapy remains a common therapeutic regimen for GC, but is frequently limited by multidrug resistance and poor intratumoral coordination of combination drugs. Targeting Menin may enhance chemotherapy sensitivity, but efficient co-delivery of Menin inhibitors and chemotherapeutics is hindered by the profound spatiotemporal pharmacokinetic decoupling of the drugs in vivo.

METHODS: We first evaluated the synergistic antitumor effect and Menin/p53-associated mechanism of BMF-219 combined with 5-fluorouracil (5-FU) in gastric cancer models. We then engineered a hierarchically assembled, cascade-responsive hyaluronic acid (HA)-decorated liposome/mesoporous silica nanoplatform (HLM@BF) for coordinated co-delivery of BMF-219 and 5-FU. The system features a glutathione (GSH)-degradable disulfide-bridged mesoporous silica core, cloaked with a pH-sensitive lipid bilayer and decorated with HA for targeting. The synergistic efficacy and biological mechanism were evaluated through bioinformatic analysis, RNA sequencing (RNA-seq), in vitro assays, and in vivo experiments.

RESULTS: BMF-219 sensitized GC cells to 5-FU-induced apoptosis through modulation of Menin- and p53-associated apoptotic signaling. HLM@BF was constructed successfully, and showed colloidal stability in serum-containing medium, pH/GSH-responsive co-delivery, enhanced CD44-associated uptake, endo/lysosomal redistribution or escape, increased tumor accumulation, and suppressed xenograft growth with favorable biosafety.

CONCLUSIONS: HLM@BF integrates Menin inhibition with 5-FU chemotherapy and enhances antitumor efficacy through Menin- and p53-associated apoptotic signaling, providing a targeted nanomedicine strategy for gastric cancer.