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Hepatocellular carcinoma (HCC) frequently suffers from compromised therapeutic efficacy due to the intrinsic apoptosis escape machinery of tumor cells and the hostile tumor microenvironment (TME). Induction of immunogenic cell death, in particular pyroptosis, represents a promising strategy to overcome these bottlenecks. Herein, we identify acyl-CoA dehydrogenase family member 11 (ACAD11) as a pivotal metabolic regulator that orchestrates the ROS/NLRP3/GSDMD pyroptosis signaling cascade. To exploit this mechanism for therapeutic intervention, we construct a biomimetic delivery nanoplatform consisting of cRGDyk-modified platelets loaded with an ACAD11 overexpression plasmid (OE-ACAD11@R-PLT). Combining the inherent tumor-homing capacity of platelets with cRGDyk-mediated active targeting, this system enables precise accumulation in HCC lesions and facilitates efficient intracellular internalization. Upon cytosolic delivery, restored ACAD11 triggers severe mitochondrial dysfunction, followed by GSDMD-dependent pyroptosis. This lytic cell death releases abundant damage-associated molecular patterns (DAMPs), which effectively remodel the immunosuppressive TME into a highly immunogenic and pro-inflammatory state, thereby eliciting systemic antitumor immunity. Collectively, this work establishes a mechanism-driven bioengineering strategy that harnesses metabolic reprogramming to surmount therapeutic resistance, offering a robust paradigm for next-generation nanomedicines against hepatocellular carcinoma.
Summary
Therapeutic outcomes for hepatocellular carcinoma (HCC) are constrained by apoptosis escape and immunosuppressive tumor microenvironments. We identified ACAD11 as a critical metabolic regulator that drives the ROS/NLRP3/GSDMD pyroptosis cascade. On this basis, a biomimetic delivery platform was engineered, where cRGDyk-modified platelets were loaded with an ACAD11 overexpression plasmid. Benefiting from the intrinsic tumor-homing property of platelets and cRGDyk-mediated active targeting, this system achieves selective accumulation and efficient cellular internalization within HCC tissues. After cytosolic delivery, restored ACAD11 triggers mitochondrial dysfunction and GSDMD-dependent pyroptosis. Massive damage-associated molecular patterns (DAMPs) are subsequently released, remodeling the immunosuppressive microenvironment into an immunogenic state to evoke systemic antitumor immunity.
This work directly links functional restoration of metabolic enzymes to pyroptosis induction, and realizes precise delivery via bioengineered carriers, offering a novel intervention strategy for apoptosis-resistant tumors. Future research may screen additional metabolic nodes that trigger pyroptosis to broaden the target spectrum. The tumor-homing feature of platelet carriers can be extended to other hypervascular tumors, while batch consistency and storage stability remain to be optimized. cRGDyk modification improves targeting accuracy, and alternative ligands can be substituted to match distinct integrin expression profiles. The antigen pool generated by pyroptosis holds potential for combination with immune checkpoint inhibitors, though the inflammatory risks arising from lytic cell death require further evaluation.
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