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Emphasis is placed on their role in regulating mitophagy and mitochondrial homeostasis via the Notch signaling pathway. The physicochemical properties of WSGC@FA@PEG\/PEI\u2010SPIONs are thoroughly characterized, demonstrating favorable biocompatibility, stable size distribution, and efficient peptide loading. In vitro experiments show that these nanoparticles significantly inhibit GA cell proliferation, migration, and invasion by downregulating mitophagy\u2010associated proteins (LC3, PINK1, and Parkin), primarily through modulation of the Notch pathway. In vivo studies, using a GA nude mouse model, confirm the therapeutic potential of WSGC@FA@PEG\/PEI\u2010SPIONs, revealing marked tumor growth inhibition and increased apoptotic activity. Collectively, the findings highlight the WSGC peptide as a promising therapeutic agent for overcoming chemotherapy resistance in GA by targeting the Notch signaling pathway and suppressing mitophagy, thereby presenting a novel strategy for polypeptide\u2010based cancer therapy.<\/jats:p>","DOI":"10.1002\/advs.202415840","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T02:41:56Z","timestamp":1755657716000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["WSGC@FA@PEG\/PEI\u2010SPIONs Mitigate Chemoresistance in Gastric Adenocarcinoma by Modulating the Notch Signaling Pathway and Mitophagy"],"prefix":"10.1002","volume":"12","author":[{"given":"Dongjian","family":"Song","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery the First Affiliated Hospital of Zhengzhou University  Zhengzhou Henan 450052 P. R. 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