A Biomimetic cRGDyk‐Engineered Platelet Nanoplatform for ACAD11 Delivery to Trigger Pyroptosis in Hepatocellular Carcinoma

Abstract

ABSTRACT The therapeutic efficacy against hepatocellular carcinoma (HCC) is frequently compromised by inherent apoptotic evasion and a hostile tumor microenvironment (TME). Inducing immunogenic cell death, particularly pyroptosis, represents a promising avenue to breach these barriers. Herein, we identify acyl‐CoA 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‐decorated platelets loaded with ACAD11‐overexpressing plasmids (OE‐ACAD11@R‐PLT). By synergizing the intrinsic tumor‐homing capabilities of platelets with cRGDyk‐mediated 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‐executed pyroptosis. This lytic cell death releases a surge of damage‐associated molecular patterns (DAMPs), effectively remodeling the immunosuppressive TME into a highly immunogenic and pro‐inflammatory milieu, thereby provoking a systemic anti‐tumor immunity. Collectively, this work establishes a mechanism‐driven, bioengineered strategy that leverages metabolic reprogramming to overcome therapeutic resistance, offering a robust paradigm for next‐generation HCC nanomedicine.