通过核苷酸修饰和甘露糖基化肽类脂质实现siIKKβ和siG12D的定向递送，可调节巨噬细胞的极化状态并重塑肿瘤细胞的代谢机制，从而为癌症治疗提供新策略。

Abstract

The nuclear factor- κ B (NF- κ B) signaling pathway serves as a critical regulator in tumorigenesis and cancer progression, with I κ B kinase β (IKK β ) emerging as a pivotal therapeutic target due to its essential role in NF- κ B activation. While siRNA-based gene silencing represents a promising strategy for IKK β inhibition, current delivery systems, including lipid nanoparticles (LNPs) and N -acetylgalactosamine (GalNAc) conjugates, remain predominantly restricted to hepatic applications. In this study, our novel delivery system composed of nucleotidyl lipid (TPS), peptidyl lipid (CLDA), and its mannosylated derivative lipid (CManDA) has been continuously used for effective extrahepatic siRNA delivery. Our optimized formulation (T/50%L/50%M, TPS:CLDA:CManDA = 21:15.75:15.75, molar ratio to siRNA) demonstrates specific tumor targeting and preferential accumulation in tumor-associated macrophages (TAMs) and malignant cells in Lewis lung carcinoma (LLC) models. Mechanistic investigations reveal that TPS/CLDA/CManDA/siIKK β mediates dual antitumor effects through: (1) Disruption of amino acid metabolic reprogramming via Myc downregulation and (2) M2-to-M1 macrophage repolarization. Furthermore, combination therapy with siRNA targeting KRAS G12D (siG12D) exhibits synergistic efficacy against KRAS G12D -mutated colon cancer through enhanced proliferation inhibition and antitumor immune activation. This study not only establishes TPS/CLDA/CManDA as a versatile platform for extrahepatic RNA interference (RNAi) therapeutics but also validates IKK β inhibition as a strategy to concurrently target tumor metabolism and immunosuppression in KRAS-driven malignancies.