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Pulmonary metastatic melanoma (PMM) is an aggressive malignancy with limited response and rapid resistance to clinical chemotherapy, radiotherapy, immunotherapy, and biological therapies. Here, we developed a targeted biomimetic drug delivery system, TP-siRC@tHyNPs, by fusing exosomes derived from engineered cells overexpressing DR5 single-chain variable fragments (DR5-Exo) with liposomes coencapsulating triptolide (TP) and CYP3A4-siRNA (TP-siRC@Lip). DR5-Exo facilitated the targeted delivery of drug to tumor cells through DR5 receptor recognition and simultaneously activated apoptotic pathways. Moreover, CYP3A4-siRNA effectively prolonged the half-life of TP, thereby enhancing its antiproliferative and pro-apoptotic effects. Mechanistic studies revealed that TP-siRC@tHyNPs induced immunogenic cell death, reprogrammed macrophage polarization, arrested cell cycle progression, and triggered apoptotic pathways. In vivo experiments demonstrated that TP-siRC@tHyNPs specifically accumulated in lung tissue, notably inhibiting the growth of PMM while exhibiting negligible toxicity in tumor-bearing mice. Overall, this study provides a promising strategy for targeting PMM treatment, improving therapeutic efficacy while reducing off-target toxicity.