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

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.