Antisense oligonucleotide-loaded nanozyme reverses tumor immune suppression through sonogenetic metabolic therapy

The immunosuppressive adenosine generated during immunogenic cell death (ICD) attenuates the ICD-elicited antitumor immune responses, while hypoxia-induced overexpression of CD73 in solid tumors exacerbates adenosine accumulation. Herein, a pioneering sonogenetic metabolic therapy was developed to activate ICD while inhibiting adenosine production. Specifically, a metal-organic framework (MOF) incorporating Ru single-atom catalytic sites was engineered to achieve high-affinity sonosensitizer loading, which was further functionalized with mPEG-d-PEI for efficient delivery of antisense oligonucleotides (ASOs) targeting CD73 mRNA. The designed system exhibited three-tiered therapeutic amplification: Ru-based catalytic sites facilitated atom-economic conversion of tumor-overproduced H₂O₂ into oxygen, alleviating tumor hypoxia. Sustained oxygen supply amplified sonodynamic effect by generating robust ROS to induce tumor apoptosis and ICD, while concurrently suppressing HIF-1α-driven CD73 upregulation. Ultrasound-responsive lysosomal disruption combined with PEI-mediated interference enabled effective lysosomal escape of ASOs, downregulating CD73 expression to inhibit adenosine production. Through immune-metabolic reprogramming of the tumor microenvironment, the approach significantly inhibited tumor growth while establishing long-term immune memory to combat pulmonary metastases in mice. Notably, beyond serving as an antitumor strategy, the developed oligonucleotide delivery system remodels metabolic homeostasis by targeting key components in signaling pathways, thereby providing new perspectives for oligonucleotide-based therapies in metabolic disease treatment.