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.
我们的前期研究发现Men1是胃癌（GC）中的一种癌基因和潜在治疗靶点。化疗仍是胃癌常用的治疗方案，但常受多药耐药和联合药物瘤内协同性差的限制。靶向Menin可能增强化疗敏感性，但Menin抑制剂与化疗药物在体内存在显著的时空药代动力学解耦，阻碍了二者的高效共递送。我们首先在胃癌模型中评估了BMF-219联合5-氟尿嘧啶（5-FU）的协同抗肿瘤效应及Menin/p53相关机制。随后，我们构建了一种层级组装、级联响应型透明质酸（HA）修饰的脂质体/介孔二氧化硅纳米平台（HLM@BF），用于BMF-219与5-FU的协同共递送。该系统以谷胱甘肽（GSH）可降解的二硫键桥连介孔二氧化硅为核心，外覆pH敏感脂质双层，并以HA修饰实现靶向。通过生物信息学分析、RNA测序（RNA-seq）、体外实验和体内实验评估了协同疗效及生物学机制。BMF-219通过调控Menin和p53相关凋亡信号通路，使胃癌细胞对5-FU诱导的凋亡敏感化。HLM@BF成功构建，在含血清培养基中表现出胶体稳定性、pH/GSH响应性共递送、增强的CD44相关摄取、内体/溶酶体重分布或逃逸、增加的肿瘤蓄积，并抑制异种移植瘤生长且具有良好的生物安全性。HLM@BF将Menin抑制与5-FU化疗整合，通过Menin和p53相关凋亡信号通路增强抗肿瘤疗效，为胃癌提供了一种靶向纳米医学策略。
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. 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. 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. 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.
Shanhu Wang, Dongsheng Li, Fanshuo Zeng, Runchuan Wang, Chhingher Ly, Jinxun Jiang, et al. 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.. Journal of experimental & clinical cancer research : CR. 2026; doi:10.1186/s13046-026-03784-6.
Shanhu Wang, Dongsheng Li, Fanshuo Zeng, Runchuan Wang, Chhingher Ly, Jinxun Jiang, et al (2026). 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.. Journal of experimental & clinical cancer research : CR. https://doi.org/10.1186/s13046-026-03784-6
Shanhu Wang, Dongsheng Li, Fanshuo Zeng, Runchuan Wang, Chhingher Ly, Jinxun Jiang, et al. 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.[J]. Journal of experimental & clinical cancer research : CR, 2026 doi:10.1186/s13046-026-03784-6.
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