The management of medulloblastoma (MB) remains a significant challenge, primarily attributed to the presence of cancer stem cells and the inadequate delivery of therapeutic agents across the blood-brain barrier. GLI, as a regulator of the hedgehog signaling pathway in normal cerebellum development, also exerts pivotal functions in MB initiation, progression, and metastasis and maintains the stemness of MB stem cells. In this study, we devised a combined therapeutic approach by integrating the BRD4 inhibitor JQ1 with the SMO inhibitor saikosaponin B1 (SSB1) to inhibit MB via regulation of GLI activation. The results suggested that JQ1 and SSB1 synergistically inhibited MB proliferation, constricted MB metastasis, and down-regulated stem cell phenotypes via reduced GLI and MYC expression. Tryptamine-derived lipid nanoparticles (NPs) transported JQ1 and SSB1 to MB tissues. The targeted NPs demonstrated prolonged drug release kinetics and significantly improved their accumulation in MB tumors. Systemic administration of drug-loaded targeted NPs significantly decreased tumor burden without hepatic toxicity in xenograft MB-bearing mice. The combination of JQ1 and SSB1 presents an innovative therapeutic paradigm for suppressing MB proliferation, recurrence, and metastasis, with the potential to drive the development of novel MB treatment strategies in the future.