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Inducing immunogenic cell death, particularly pyroptosis, represents a promising avenue to breach these barriers. Herein, we identify acyl\u2010CoA dehydrogenase family member 11 (ACAD11) as a pivotal metabolic regulator that drives the ROS\/NLRP3\/GSDMD pyroptotic signaling axis. To therapeutically exploit this mechanism, we engineered a biomimetic delivery nanoplatform comprising cRGDyk\u2010decorated platelets loaded with ACAD11\u2010overexpressing plasmids (OE\u2010ACAD11@R\u2010PLT). By synergizing the intrinsic tumor\u2010homing capabilities of platelets with cRGDyk\u2010mediated active targeting, this system ensures precise accumulation in HCC tissues and facilitates efficient intracellular payload internalization. Upon cytosolic delivery, restored ACAD11 triggers severe mitochondrial dysfunction and subsequent GSDMD\u2010executed pyroptosis. This lytic cell death releases a surge of damage\u2010associated molecular patterns (DAMPs), effectively remodeling the immunosuppressive TME into a highly immunogenic and pro\u2010inflammatory milieu, thereby provoking a systemic anti\u2010tumor immunity. Collectively, this work establishes a mechanism\u2010driven, bioengineered strategy that leverages metabolic reprogramming to overcome therapeutic resistance, offering a robust paradigm for next\u2010generation HCC nanomedicine.<\/jats:p>","DOI":"10.1002\/advs.78219","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:59:04Z","timestamp":1791518344000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Biomimetic cRGDyk\u2010Engineered Platelet Nanoplatform for ACAD11 Delivery to Trigger Pyroptosis in Hepatocellular Carcinoma"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0564-8158","authenticated-orcid":false,"given":"Hongyi","family":"Bao","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine Wuxi Medical Center The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Nanjing Medical University  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