{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:55:42Z","timestamp":1792292142177,"version":"4.4.0"},"reference-count":51,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"30","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,7,25]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1126\/sciadv.adv6990","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T17:58:39Z","timestamp":1753293519000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":39,"title":["Engineering hybrid nanoparticles for targeted codelivery of triptolide and\n                    <i>CYP3A4<\/i>\n                    -siRNA against pulmonary metastatic melanoma"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4021-6485","authenticated-orcid":true,"given":"Yongwei","family":"Gu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, 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